3-phenyl-2-propeneamine derivatives, their preparation and compositions containing them

ABSTRACT

The invention provides compounds of formula: ##STR1## in which R=H, halogen, alkyl, alkyloxy, alkythio, NH 2 , alkylamino, dialkylamino or CF 3 , R 3  =H or alkyl, either R 4  and R 5  =H and R 1  and R 2  =H or alkyl, optionally substituted by alkenyl (2 to 4 C) or alternatively R 1  and R 2  form together a saturated heterocyclic ring containing 4 to 7 ring members and optionally containing another heteroatom such as O, S or N optionally substituted by alkyl, or R 4  =H, R 1  =H or alkyl and R 2  and R 5  together form an alkylene (3 to 4 C) radical and (i) either A=alkyl or phenyl which is unsubstituted or substituted by one or two substituents chosen from halogen, alkyl, alkyloxy, alkylthio, NH 2 , alkylamino, dialkylamino, NO 2  or CF 3  or alternatively A=pyridyl, benzyl or cycloalkyl (3 to 6C), Y=S, SO or SO 2  or a radical: ##STR2## in which R 6  =H or alkyl and R 7  =H or alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl or benzoyl, optionally substituted by one or two halogen, alkyl, alkyloxy, alkylthio, NH 2 , alkylamino, dialkylamino, NO 2  or CF 3  groups, (ii) or Y and A together form a 1-hydroxycycloalkyl radical, the ring of which contains 5 or 6 C, optionally joined to a benzene ring, it being understood that the alkyl radicals and alkyl parts contain 1 to 4 C as a straight or branched chain, and that the invention relates to all the possible geometric and optical isomers as well as their mixtures. 
     These compounds are useful as antidepressants.

The present invention relates to phenylpropeneamine derivatives andtheir preparation and to pharmaceutical compositions containing thesame.

More particularly, the invention provides the 3-phenyl-2-propeneaminederivatives of formula: ##STR3## in which R denotes hydrogen, halogen,alkyl, alkyloxy, alkylthio, amino, alkylamino, dialkylamino ortrifluoromethyl, R₃ denotes hydrogen or alkyl; either R₄ and R₅ eachdenote hydrogen and R₁ and R₂, which are identical or different, eachdenote hydrogen or alkyl which is unsubstituted or substituted byalkenyl of 2 to 4 carbon atoms, or R₁ and R₂ form together with thenitrogen atom to which they are linked a saturated heterocyclic radicalof 4 to 7 ring atoms and optionally containing another heteroatom suchas oxygen, sulphur or nitrogen which is unsubstituted or substituted byalkyl, or R₄ denotes hydrogen, R₁ denotes hydrogen or alkyl and R₂ andR₅ form together an alkylene radical of 3 or 4 carbon atoms and either(i) A denotes alkyl or phenyl which is unsubstituted or substituted byone or two substituents chosen from halogen, alkyl, alkyloxy, alkylthio,amino, alkylamino, dialkylamino, nitro and trifluoromethyl or A denotespyridyl, benzyl, or cycloalkyl of 3 to 6 carbon atoms and Y denotessulphur, sulphinyl or sulphonyl or a radical of formula: ##STR4## inwhich R₆ denotes hydrogen or alkyl and R₇ denotes hydrogen,alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl or benzoyl which isunsubstituted or substituted by one or two substituents chosen fromhalogen, alkyl, alkyloxy, alkylthio, amino, alkylamino, dialkylamino,nitro and trifluoromethyl or (ii) Y and A together form a1-hydroxycycloalkyl radical the ring of which contains 5 or 6 carbonatoms, optionally coupled to a benzene ring, it being understood that inthe preceding definitions and in those which follow, the alkyl radicalsand alkyl parts contain 1 to 4 carbon atoms as a straight or branchedchain and that the invention relates to all the possible geometric andoptical isomers and their mixtures.

According to the invention, the compound of formula (I) in which Ydenotes a radical of formula (II) in which R₆ is defined as previouslyand R₇ denotes hydrogen and A, R, R₁ and R₂ are defined as previously,except that R₁ and/or R₂ is not hydrogen, and which are in the Zconfiguration, are prepared by the reaction of a compound of formula:

    A--CO--R.sub.6                                             (III)

in which A and R₆ are as defined previously, with a carbanion of generalformula: ##STR5## in which the symbols are as defined previously, exceptthat R₁ and/or R₂ is not hydrogen.

The reaction is generally carried out in an inert organic solvent suchas hexane, pentane, ethyl ether, 1,2-dimethoxyethane or tetrahydrofuranor a mixture of these solvents, at a temperature in the region of -30°C.

The carbanion of formula (IV) can be obtained according to one of thefollowing methods, depending on the nature of the radicals:

(A) When R is defined as previously, except for denoting halogen ortrifluoromethyl, and R₁ and R₂ are defined as previously, except that R₁and/or R₂ is not hydrogen, it may be obtained by reacting anorganometallic base with a compound of general formula: ##STR6## inwhich R is defined as previously, but is not halogen or trifluoromethyl,and the symbol Iris denotes the 2,4,6-triisopropylphenyl radical,followed by the reaction of a product of formula: ##STR7## in which thesymbols are defined as previously, except that R₁ and/or R₂ is nothydrogen, and X.sup.⊖ denotes a halide (preferably iodide) ion, toobtain an intermediate of formula: ##STR8## in which the symbols aredefined as previously, except that R is not halogen or trifluoromethyland R₁ and/or R₂ is not hydrogen, and the symbol Tris is defined aspreviously, this intermediate of general formula (VII) being thentreated with an organometallic base to give, after fragmentation, thecorresponding carbanion of general formula (IV).

In practice, it is advantageous to dissolve the compound of formula (V)in an inert solvent such as 1,2-dimethoxyethane, to treat the solutionobtained with two equivalents of butyllithium dissolved in hexane,operating at a temperature of between -70° and -78° C., to condense theproduct of formula (VI) at a temperature in the region of -50° C., totreat the intermediate of general formula (VII) which is obtained withone equivalent of butyllithium dissolved in hexane at a temperature ofbetween -70° and -78° C. and to allow the temperature to rise to about0° C. In this case, the corresponding carbanion of general formula (IV)is obtained in solution in a mixture of 1,2-dimethoxyethane and hexane.

The products of general formula (V) may be prepared by reaction of2,4,6-triisopropylbenzenesulphonylhydrazine with a product of generalformula: ##STR9## in which R and R₃ are defined as previously, exceptfor R denoting a halogen atom or a trifuloromethyl radical, byproceeding according to the method described by M. F. Lipton and R. H.Shapiro, J. Org. Chem. 43, 1409 (1978).

(B) When the symbols R, R₁, R₂ and R₃ are defined as in the generalformula (IV), and R₄ and R₅ denote a hydrogen atom, the carbanion may beobtained by reaction of an organometallic base with a product of generalformula: ##STR10## in which the symbols have the definition given forthe carbanion of general formula (IV).

In practice, it is advantageous to employ butyllithium dissolved inhexane as an organometallic base and to carry out the reaction in aninert organic solvent such as a hydrocarbon (for example pentane) or anether (for example ethyl ether) at a temperature of between -78° and-10° C. In this case, the carbanion of general formula (IV) is obtainedin solution in a mixture of pentane and hexane or in a mixture of ethylether and hexane.

The products of general formula (IX) can be prepared starting from aproduct of general formula: ##STR11## in which R, R₁, R₂ and R₃ have thedefinitions given previously for the carbanion of general formula (IV),by successive reaction with phosphorus oxybromide, methanol and analkali metal borohydride such as sodium cyanoborohydride.

The operation is generally carried out in an organic solvent such asmethylene chloride, at a temperature of between 0° and 10° C.

The products of general formula (X) can be prepared by employing ormodifying the method described by H. Meerwein, W. Florian, N. Schon andG. Stopp, Ann. Chem., 641, 1, (1961).

(C) When R is defined as previously, except for denoting a halogen atomor a trifuloromethyl radical, and R₁ and/or R₂ are defined aspreviously, except for denoting a hydrogen atom, the carbanion can beobtained by reaction of an organometallic base with a product of generalformula: ##STR12## in which R, R₁, R₂, R₃, R₄ and R₅ are defined aspreviously, except for R denoting a halogen atom or a trifluoromethylradical and for R₁ and/or R₂ denoting a hydrogen atom, and the symbolTris is defined as previously in the general formula (V), to obtain anintermediate of general formula: ##STR13## in which R, R₁, R₂, R₃, R₄,R₅ and Tris have the corresponding definitions, this intermediate thenbeing fragmented to give the corresponding carbanion of general formula(IV).

In practice the organometallic base employed is n-butyllithium ortert.-butyllithium dissolved in an aliphatic hydrocarbon such as hexaneor pentane, and the reaction is carried out in an inert organic solventsuch as 1,2-dimethoxyethane at a temperature of between -78° and -70°C., and then the temperature is allowed to rise to about 0° C. In thiscase, the corresponding carbanion of general formula (IV) is obtained insolution in a mixture of 1,2-dimethoxyethane and hexane or1,2-dimethoxyethane and pentane.

The products of general formula (XI) may be prepared by reaction of2,4,6-triisopropylbenzenesulphonylhydrazine with a product of generalformula: ##STR14## in which R, R₁, R₂, R₃, R₄ and R₅ are defined aspreviously, except for R denoting a halogen atom or a trifluormethylradical and for R₁ and/or R₂ denoting a hydrogen atom.

The operation is generally carried out in an organic solvent such as analcohol containing dissolved hydrogen chloride.

The products of general formula (XIII) can be prepared by employing ormodifying the method described by C. E. Maxwell, Org. Syntheses, Coll.Vol. III, John Wiley & Sons, London (1955) page 305.

According to the invention, the products of general formula (I) in whichY denotes a radical of general formula (II) in which R₆ and R₇ denote ahydrogen atom, A is defined earlier under (i), R₁ denotes a hydrogenatom, R₂ denotes a hydrogen atom or an alkyl radical optionallysubstituted by an alkenyl radical containing 2 to 4 carbon atoms, Rdenotes a hydrogen atom, R₃ is defined as previously and R₄ and R₅denote a hydrogen atom, and which are in the Z configuration, may beprepared by opening the dihydrofuran ring in a product of generalformula: ##STR15## in which A is defined as previously under (i) and R'₂denotes an alkyl radical optionally substituted by an alkenyl radicalcontaining 2 to 4 carbon atoms and R₃ is defined as previously.

Generally, the opening of the dihydrofuran ring is carried out with theaid of an alkali metal borohydride such as sodium borohydride in amixture of water and alcohol, for example methanol-water, at atemperature of between 0° and 20° C., preferably at a temperature in theregion of 5° C.

When the intention is to use this process to obtain a product of generalformula (I) in which Y denotes a radical of general formula (II) inwhich R₆ and R₇ denote a hydrogen atom, A is defined as previously under(i), R, R₁, R₂, R₄ and R₅ denote a hydrogen atom and R₃ is defined aspreviously, and which are in the Z configuration, it is necessary tostart from a product of general formula (XIV) in which R'₂ denotes analkyl radical optionally substituted by an alkenyl radical containing 2to 4 carbon atoms, and then to remove the said radical according to aknown method, for example the method of D. Picq, M. Cottin, D. Anker andH. Pacheco, Tet. Letters (1983), 1399.

The products of general formula (XIV) can be prepared by reaction of aproduct of general formula (XV), in equilibrium with its tautomericform, ##STR16## in which R'₂ denotes an alkyl radical optionallysubstituted by an alkenyl radical containing 2 to 4 carbon atoms and R'denotes an alkyl (preferably ethyl) radical with a product of generalformula: ##STR17## in which Y denotes a radical of general formula (II)in which R₆ and R₇ denote a hydrogen atom and A is defined as previouslyunder (i).

The operation is generally carried out in an organic solvent such astetrahydrofuran in the presence of a condensing agent such as an alkalimetal hydride, at a temperature of between 20° and 100° C., preferablyat a temperature in the region of 60° C.

The products of general formula (XV) can be prepared according to themethod described by N. D. Dawson and A. Burger, J. Am. Chem. Soc. 74,5312, (1952).

The products of general formula (XVI) can be prepared by employing ormodifying the methods of L. R. Krepski, S. M. Heilmann and J. K.Rasmussen, Tet. Letters, 4075, (1983) or of R. E. Koenigkramer and H.Zimmer, Tet. Letters, 1017, (1980).

According to the invention, the products of general formula (I) in whichY denotes a sulphur atom, R₄ and R₅ denote a hydrogen atom, A is definedas previously under (i) and the remaining symbols are defined aspreviously, except for R₁ and/or R₂ denoting a hydrogen atom, and whichare in the Z or E configuration, can be prepared by reaction of amercaptan of general formula:

    A--SH                                                      (XVII)

in which A is defined as previously under (i) with a product of generalformula: ##STR18## in which R, R₁, R₂, and R₃ are defined as previously,except for R₁ and/or R₂ denoting a hydrogen atom, Hal denotes a halogenatom such as chlorine or bromine, and X'.sup.⊖ denotes any anion such ashalide, chlorate, perchlorate, phosphate or fluoroborate, followed by areduction of the intermediate obtained, of general formula: ##STR19## inwhich the symbols have the corresponding meanings.

The reaction of the product of formula (XVII) with the product offormula (XVIII) is generally carried out in a chlorinated solvent, analcohol or an ether, or a mixture of these solvents, in the presence ofan acid-acceptor such as triethylamine, at a temperature of between 0°and 20° C.

The reduction of the intermediate of general formula (XIX) is generallycarried out with the aid of an alkali metal borohydride such as sodiumborohydride or sodium cyanoborohydride, in the solvent in which thecondensation of the product of general formula (XVII) with the productof general formula (XVIII) has been carried out.

The products of general formula (XVIII) can be prepared by reaction of aphosphorus oxyhalide with a product of general formula (X) in which R,R₁ and R₂ are defined as previously, except for R₁ and/or R₂ denoting ahydrogen atom.

The operation is generally carried out in a chlorinated solvent such asmethylene chloride, at a temperature of between 0° and 20° C.

In order to carry out the reaction consisting in reacting the product ofgeneral formula (XVII) with the product of general formula (XVIII), itis not necessary for the product of general formula (XVIII) to have beenisolated. After the product of general formula (XVIII) has been preparedas stated above, it suffices to add the product of general formula(XVII) and an acid-acceptor to the reaction mixture and to continue thereaction at a temperature of between 0° and 20° C., and then to reducein situ the intermediate of general formula (XIX) as set out above.

According to the invention, the products of general formula (I) in whichY denotes a sulphur atom, R₄ and R₅ denote a hydrogen atom, A is definedas previously under (i) and the remaining symbols are defined aspreviously, and which are in the Z or E configuration, can also beprepared by reaction of ammonia or an amine of general formula:##STR20## in which R₁ and R₂ are defined as previously, with an aldehydeof general formula: ##STR21## in which A is defined as previously under(i) and R and R₃ are defined as previously, and which is in the Z or Econfiguration.

The operation is generally carried out in an organic solvent such as analcohol, such as methanol, in the presence of an alkali metalborohydride such as sodium cyanoborohydride and of molecular sieves, ata temperature in the region of 20° C.

The products of general formula (XXI) can be prepared by reaction of amercaptan of general formula (XVII) defined as previously with a productof general formula: ##STR22## in which R and R₃ are defined aspreviously and Hal denotes a halogen atom such as chlorine or bromineand which is in the E or Z configuration.

The operation is generally carried out in an organic solvent such asmethylene chloride in the presence of an acid-acceptor such astriethylamine, at a temperature of between 0° and 20° C.

The product of general formula (XXII) can be prepared by employing ormodifying the method of C. M. Beaton, N. B. Chapman and K. Klarke, J.Chem. Soc. Perkin I, 2355, (1976).

According to the invention, the products of general formula (I) in whichY denotes a radical of general formula (II) in which R₇ denotes ahydrogen atom or alternatively Y is defined as under (ii) and theremaining symbols are defined as previously, and which are in the Econfiguration, can be prepared by reaction of an organomagnesiumderivative of general formula: ##STR23## in which R is defined aspreviously and Xo denotes a halogen atom (preferably bromine) with aproduct of general formula: ##STR24## in which the symbols are definedas previously.

The operation is carried out according to methods known to those skilledin the art for reacting an organomagnesium derivative with an acetylenederivative without affecting the remainder of the molecule.

When R₁ and/or R₂ denote a hydrogen atom, it is obvious to the personskilled in the art that the corresponding amine function will need to beprotected in the product of general formula (XXIV) before reaction withthe organomagnesium derivative of formula (XXIII). It is possible toemploy any blocking means known to the person skilled in the art toprotect a primary or secondary amine, which does not affect theremainder of the molecule and which can be removed subsequently.

The products of general formula (XXIV) can be prepared by reaction of aproduct of general formula:

    A--CO--R.sub.3                                             (XXV)

in which A and R₃ are defined as previously with a propargylamine ofgeneral formula: ##STR25## in which R₁, R₂, R₄ and R₅ are defined aspreviously, except for R₁ and R₂ denoting, together or separately, ahydrogen atom.

The reaction is generally carried out in an inert organic solvent suchas 1,2-dimethoxyethane, at a temperature of between -40° and 0° C.,after the propargylamine of general formula (XXVI) has been metalated byany known means. The metalation can be carried out, for example, withthe aid of an organometallic base such as n-butyllithium dissolved inhexane at a temperature in the region of -70° C.

The products of general formula (XXVI) can be prepared by reaction of anamine of general formula (XX) defined as previously with propargylbromide by employing or modifying the method of M. Gaudemar, Ann. Chim.(France) 13, 161, (1956).

According to the invention, the products of general formula (I) in whichY denotes a radical of general formula (II) in which R₇ denotes analkylcarbonyl, alkoxycarbonyl or benzoyl radical optionally substitutedby one or two substituents chosen from halogen atoms and alkyl,alkyloxy, alkylthio, amino, alkylamino, dialkylamino, nitro ortrifluoromethyl radicals, and the remaining symbols are defined aspreviously, can be obtained by reaction of a product of general formula:

    R'.sub.7 --X.sub.1                                         (XXVII)

in which R'₇ denotes an alkylcarbonyl, alkoxycarbonyl or benzoyl radicaloptionally substituted by one or two substituents chosen from halogenatoms and alkyl, alkyloxy, alkylthio, amino, alkylamino, dialkylamino,nitro, or trifluoromethyl radicals and X₁ denotes a reactive esterresidue such as a halide with a product of general formula (I) in whichY denotes a radical of general formula (II) in which R₇ denotes ahydrogen atom and the remaining symbols are defined as previously, thatis to say a product of general formula: ##STR26##

The operation is carried out using any method known to those skilled inthe art for acylating a secondary or tertiary alcohol, for example byworking in pyridine at a temperature of between 0° and 50° C., or in aninert solvent such as a chlorinated solvent, in the presence of anacid-acceptor when X₁ denotes a halogen atom.

It is clear to the person skilled in the art that, when R₁ and/or R₂denote a hydrogen atom, it is necessary to block the corresponding aminefunction before reacting the product of general formula (XXVII) with theproduct of general formula (XXVIII). The amine function is thenliberated after the process has been carried out. Blocking of the aminecan be carried out, for example, in the form of a tert.-butyloxycarbonylradical, readily capable of cleavage by known methods without affectingthe radical R₇ introduced into the molecule by using the presentprocedure.

According to the invention, the products of general formula (I) in whichY denotes a sulphur atom or a radical of general formula (II) defined aspreviously, R₄ and R₅ denote a hydrogen atom and the remaining symbolsare defined as previously, and which are in the E or Z configuration,can be prepared by reaction of ammonia, an amine-precursor or an amineof general formula (XX) with a product of general formula: ##STR27## inwhich A is defined as previously under (i) R and R₃ are defined aspreviously and

(a) either X denotes a chlorine atom and Y' denotes a sulphur atom or aradical of general formula (II) in which R₆ is defined as previously andR₇ denotes an alkyloxycarbonyl radical,

(b) or X denotes a bromine atom and Y' denotes a sulphur atom,

and which is in the E or Z configuration, optionally followed by ahydrolysis when the intention is to obtain the product of generalformula (I) in which Y denotes a radical of general formula (II) inwhich R₇ denotes a hydrogen atom, R₄ and R₅ denote a hydrogen atom andthe remaining symbols are defined as previously.

The operation is generally carried out in an organic solvent such as analcohol, such as ethanol or dimethylformamide, by operating underpressure if appropriate, at a temperature which may be between 0° and100° C.

The subsequent optional hydrolysis can be carried out by any means knownto those skilled in the art for removing an alkylcarbonyl,alkyloxycarbonyl, or benzoyl radical optionally substituted by one ortwo substituents chosen from halogen atoms and alkyl, alkyloxy,alkylthio, amino, alkylamino, dialkylamino, nitro or trifluoromethylradicals or alkylaminocarbonyl employed to block an alcohol function. Itis thus possible to operate in a solvent such as an alcohol in thepresence of a base, such as sodium hydroxide or an alkali metalcarbonate.

An amine-precursor as employed in the present method is understood tomean a product such as sodium azide which, after condensation with theproduct of general formula (XXIX) can produce the required amine by asubsequent operation which is known to those skilled in the art; in thecase of sodium azide, the product of its condensation with the productof general formula (XXIX) is treated with 1,3-propanedithiol in thepresence of an acid-acceptor such as triethylamine.

The products of general formula (XXIX) defined as previously under (a)can be obtained by reaction of an alkyl chloroformate with a product ofgeneral formula: ##STR28## in which R, R₁, R₂, R₃ and A are defined aspreviously and Y' denotes a sulphur atom or a radical of general formula(II) in which R₆ and R₇ are defined as previously and which is in the Eor Z configuration.

The operation is generally carried out in an inert organic solvent suchas an aromatic hydrocarbon, such as benzene or toluene, or a chlorinatedsolvent such as carbon tetrachloride, at a temperature of between 60° C.and the reflux temperature of the reaction mixture.

The products of general formula (XXIX) defined as previously under (b)can be obtained by reaction of cyanogen bromide with a product ofgeneral formula (I_(A)) in which R, R₁, R₂, R₃ and A have thecorresponding meanings and Y' denotes a sulphur atom, and which is inthe E or Z configuration.

The operation is generally carried out in a chlorinated solvent such asmethylene chloride or chloroform, at a temperature of between 0° and 60°C.

The products of general formula (I_(A)) which are products according tothe invention can be prepared by one of the methods described earlier.

According to the invention, the products of general formula (I) in whichY denotes a radical of general formula (II) in which R₇ denotes analkylaminocarbonyl radical and the remaining symbols are defined aspreviously may be obtained by reaction of an isocyanate of generalformula:

    O═C═N--R.sub.7 "                                   (XXX)

in which R"₇ denotes an alkyl radical with a product of general formula(I) in which Y denotes a radical of general formula (II) in which R₇denotes a hydrogen atom and the remaining symbols are defined aspreviously, that is to say a product of general formula (XXVIII).

The operation is carried out by any method known to the person skilledin the art for preparing a carbamate from an isocyanate and an alcohol,for example by working in a chlorinated solvent such as chloroform at atemperature of between 0° C. and the reflux temperature of the reactionmixture.

It is obvious to the person skilled in the art that, when R1 and/or R2denote a hydrogen atom, it is necessary to block the corresponding aminefunction before reacting the product of general formula (XXX) with theproduct of general formula (XXVIII). The amine function is thenliberated after the process has been carried out. Blocking of the aminemay be, for example, in the form of a tert.-butyloxycarbonyl radical,readily capable of cleavage according to the known methods withoutaffecting the radical R₇ introduced into the molecule using the presentprocedure.

According to the invention, the products of general formula (I) in whichY denotes a sulphinyl or sulphonyl radical and the remaining symbols aredefined as previously can be prepared by oxidation of a product ofgeneral formula (I) in which Y denotes a sulphur atom and the remainingsymbols are defined as previously, that is to say a product of generalformula: ##STR29##

The oxidation can be carried out by employing an agent which isgenerally employed to convert a sulphide to a sulphoxide or to asulphone, by operating in a suitable solvent, without affecting theremainder of the molecule. For example, it is possible to employhydrogen peroxide in acetone or acetic acid, an alkali metal periodatein an alcohol or acetonitrile, a carboxylic peroxyacid (peracetic,perbenzoic, m-chloroperbenzoic, p-nitroperbenzoic or perphthalic acid)in an ether (dioxane, tetrahydrofuran), or a chlorinated solvent(methylene chloride, dichloroethane), acetic acid or a mixture of thesesolvents.

When the intention is to produce the sulphoxide, that is to say theproduct of general formula (I) in which Y denotes a sulphinyl radical,it is particularly advantageous to work in methylene chloride in thepresence of two equivalents of oxidising agent (preferablym-chloroperbenzoic acid) at a temperature in the region of 0° C.,preferably in the presence of an equivalent of an inorganic acid.

When the intention is to produce the sulphone, that is to say theproduct of general formula (I) in which Y denotes a sulphonyl radical,it is particularly advantageous to work in the presence of at least 3equivalents of oxidising agent at a temperature of between 20° C. andthe reflux temperature of the reaction mixture.

It is obvious to the person skilled in the art that each time that oneof the procedures set out above employs an organometallic derivative andreactant product molecules containing an amino function, the latter mustbe protected beforehand. For this purpose, the procedure follows themethods known to those skilled in the art. For example, the aminofunction can be protected by means of a labile silyl derivative which isreadily removed when the reaction has ended.

The new products of general formula (I) can be purified by the usualmethods such as crystallisation, chromatography or successiveextractions in an acidic and basic medium.

When the products of general formula (I) or their intermediates whichare mentioned in the present description exist in E and Z forms as amixture in the reaction medium, their separation can be carried out byany means known to the person skilled in the art, particularly bychromatography.

The new products of general formula (I) can be optionally converted intosalts of addition with acids, by reaction with an acid in an organicsolvent such as an alcohol, a ketone, an ester or a chlorinated solvent;the salt which is formed precipitates, optionally after its solution hasbeen concentrated; it is isolated by filtration or decantation.

The new products of general formula (I) and their salts exhibitinteresting pharmacological properties which make them useful asantidepressants.

They have been shown to be active particularly in the test forantagonist action against tetrabenazine-induced depression in the mouseat dosages of between 1 and 100 mg/kg by oral route.

Their lethal dose LD₅₀ is generally between 50 and 900 mg/kg by oralroute.

Those of special importance are the products of general formula (I) inwhich R denotes a hydrogen, halogen, alkyl, alkyloxy, alkylthio, amino,alkylamino, dialkylamino or trifluoromethyl, R₃ denotes hydrogen oralkyl, and either R₄ and R₅ denote hydrogen and R₁ and R₂ which areidentical or different, each denote hydrogen or alkyl optionallysubstituted by an alkenyl radical containing 2 to 4 carbon atoms, or R₁and R₂ form together with the nitrogen atom to which they are linked asaturated heterocyclic radical containing 4 to 7 ring atoms (preferably5 or 6 ring members), or R₄ denotes hydrogen, R₁ denotes hydrogen oralkyl and R₂ and R₅ together form an alkylene radical containing 3 or 4carbon atoms (preferably 3 carbon atoms), and either (i) A denotes alkylor phenyl which is unsubstituted or substituted by one or twosubstituents chosen from halogen, alkyl, alkyloxy and trifluoromethylradicals, or A denotes pyridyl, benzyl or cycloalkyl containing 3 to 6carbon atoms, Y denotes sulphur, sulphinyl, or a radical of formula:##STR30## in which R₆ denotes hydrogen or alkyl and R₇ denotes hydrogen,alkylcarbonyl, alkyloxycrbonyl, benzoyl or alkylaminocarbonyl, or (ii) Yand A together form a 1-hydroxycycloalkyl radical the ring of whichcontains 5 or 6 carbon atoms, optionally combined with a benzene ring,in the Z or E form, it being understood that in the precedingdefinitions the alkyl radicals and alkyl parts contain 1 to 4 carbonatoms each, as a straight or branched chain.

Those of more particular importance are the products of general formula(I) in which R denotes hydrogen, halogen, alkyl, alkyloxy, alkylthio,amino, alkylamino, dialkylamino or trifluoromethyl, R₃ denotes hydrogen,R₄ and R₅ denote hydrogen, and R₁ and R₂, which are identical ordifferent, each denote hydrogen, or alkyl optionally substituted by analkenyl radical of 2 to 4 carbon atoms; and A denotes alkyl or phenyl,which is unsubstituted or substituted by one or two substituents chosenfrom halogen and alkyl, or alternatively A denotes pyridyl or cycloalkylof 3 to 6 carbon atoms, Y denotes sulphur atom, or a radical of formula:##STR31## in which R₆ denotes hydrogen and R₇ denotes hydrogen oralkylcarbonyl, in the Z form, it being understood that in the precedingdefinitions the alkyl radicals and alkyl parts contain 1 to 4 carbonatoms as a straight or branched chain.

The following products are of very special interest:

4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z)

4-methylamino-1,2-diphenyl-2-buten-1-ol (Z)

1-(3-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

1-(3-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

1-(3-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol (Z)

4-amino-1,2-diphenyl-2-buten-1-ol (Z)

3-(2-chlorophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z)

2-(3-chlorophenyl)-1-(3-fluorophenyl)-4-dimethylamino-2-buten-1-ol (Z)

2-(3-chlorophenyl)-4-dimethylamino-1-phenylthio-1-propene (Z)

1-(3-fluorophenyl)-4-methylamino-2-phenyl-2-buten-1-ol (Z)

3-amino-1-phenyl-1-phenylthio-1-propene (Z)

1-(4-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

1-(4-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

4-acetoxy-1-dimethylamino-3,4-diphenyl-2-butene (Z)

4-allylamino-1,2-diphenyl-2-buten-1-ol (Z)

1-(2-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

3-(4-fluorophenylthio)-3-phenyl-2-propene (Z)

1-(2-fluorophenyl)-2-phenyl-2-buten-1-ol (Z)

1-dimethylamino-5-methyl-3-phenyl-2-hexen-4-ol (Z)

1-methylamino-3-phenyl-3-phenylthio-2-propene (Z)

1-cyclohexyl-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

4-dimethylamino-2-phenyl-1-(2-pyridyl)-2-buten-1-ol (Z)

4-dimethylamino-1-(4-fluorophenyl)-2-buten-1-ol (Z)

1-(2-chloro-6-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z).

2-Propeneamines with antidepressant properties are known for BelgianPat. No. 781105; however, none of the products disclosed contains in itsmolecule a radical Y such as defined in the present invention andnothing in the prior art would prompt the person skilled in the art tointroduce such a radical.

For medicinal use, new products of general formula (I) can be employedas such or, where appropriate, in the form of pharmaceuticallyacceptable salts, that is to say those which are non toxic in thedosages employed.

As examples of pharmaceutically acceptable salts mention can be made ofaddition salts with inorganic acids (such as hydrochlorides, sulphates,nitrates or phosphates), or organic acids (such as acetates,propionates, succinates, benzoates, fumarates, maleates,methanesulphonates, isethionates, theophyllineacetates, salicylates,phenolphthaleinates, methylenebis-β-oxynaphthoates), or substitutedderivatives of these compounds.

The following Examples illustrate the invention. In some examples, theproducts are purified by "flash chromatography"; this refers to apurification method in which a short chromatography column is employed,operating at an intermediate pressure (50 kPa), using a silica ofparticle size 40-63 μm, as described by W. C. Still, M. Kahn and A.Mitra, J. Org. Chem., 43, 2923, (1978)

In the NMR spectra which are given, the lower case letters have thefollowing meanings: s=singlet, d=doublet, t=triplet, m=multiplet.

EXAMPLE 1

A 1.5M solution (83 cc) of n-butyllithium in hexane is added, at atemperature in the region of -75° C., to a solution of acetophenone2,4,6-triisopropylbenzenesulphonylhydrazone (24 g) in1,2-dimethoxyethane (1000 cc) kept under a nitrogen atmosphere.N,N-dimethylmethyleneammonium iodide (11.1 g) is added to the orangesolution obtained; the suspension obtained is stirred vigorously for 20minutes at a temperature in the region of -50° C.; a 1.5M solution (41.5cc) of n-butyllithium in hexane is then added at a temperature in theregion of -75° C. The reaction mixture is heated slowly up to atemperature in the region of 0° C. Starting from -30° C., a gas releaseis noted which drops almost to zero when the temperature is in theregion of 0° C. The reaction mixture is then cooled to a temperature inthe region of -30° C. Benzaldehyde (7.7 g) dissolved in1,2-dimethoxyethane (200 cc) is then added to it and stirring iscontinued for 2 hours at a temperature in the region of 20° C. Distilledwater (250 cc), concentrated hyrochloric acid (50 cc) and ethyl ether(300 cc) are then added in succession. The aqueous phase is separated;the organic phase is extracted with a 1N aqueous solution ofhydrochloric acid (125 cc). The aqueous phases are combined, madealkaline with a 10N aqueous solution of sodium hydroxide to a pH in theregion of 11 and are then extracted with ethyl acetate (3×200 cc). Theorganic phases are combined, dried over magnesium sulphate, filtered andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.;the residue obtained is dissolved in a mixture of ethyl ether (140 cc)and ethanol (70 cc); a 3.5N solution (20 cc) of hydrochloric acid gas inethyl ether is added to the solution obtained. The solid formed isseparated by filtration and then recrystallized from acetonitrile.4-Dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (10 g) isthus obtained in the form of a white powder melting at 178° C.

Acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone can be preparedby the method described by M. F. Lipton and R. H. Shapiro. J. Org.Chem., 43, 1409, (1978).

EXAMPLE 2

By using a method similar to that described in Example 1, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (36.1 g),N,N-dimethylmethyleneammonium iodide (18.5 g) andcyclohexanecarboxaldehyde (11.2 g),1-cyclohexyl-4-dimethylamino-2-phenyl-2-buten-1-ol (Z) hydrochloride(7.5 g) is obtained, after recrystallisation from acetonitrile, in theform of a white powder melting at 222° C.

EXAMPLE 3

By using a method similar to that described in Example 1, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and 4-chlorobenzaldehyde(4.7 g), 1-(4-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)hydrochloride (3 g) is obtained, after recrystallisation from acetone,in the form of a white powder melting at 170° C.

EXAMPLE 4

By using a method similar to that described in Example 1, but startingfrom acetone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and acetophenone (4 g),4-dimethylamino-1,2-diphenyl-1-methyl-2-buten-1-ol (Z) hydrochloride(2.5 g) is obtained, after recrystallisation from acetone, in the formof a white powder melting at 160° C.

EXAMPLE 5

By using a method similar to that described in Example 1, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and 4-bromobenzaldehyde(6.1 g), 1-(4-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)hydrochloride (2.1 g) is obtained, after recrystallisation fromacetonitrile, in the form of a white powder melting at 163° C.

EXAMPLE 6

By using a method similar to that described in Example 1, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and phenylacetaldehyde (3.9g), 5-dimethylamino-1,3-diphenyl-3-penten-2-ol (Z) hydrochloride (2.3 g)is obtained, after recrystallisation from ethanol, in the form of awhite powder melting at 220° C.

EXAMPLE 7

By using a method similar to that described in Example 1, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and3-trifluoromethylbenzaldehyde (5.7 g),4-dimethylamino-2-phenyl-1-(3-trifluoromethylphenyl)-2-buten-1-ol (Z)hydrochloride (2.1 g) is obtained, after recrystallisation from acetone,in the form of white crystals melting at 180° C.

EXAMPLE 8

By using a method similar to that described in Example 1, but startingfrom 4-methylacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(12.1 g), N,N-dimethylmethyleneammonium iodide (6.1 g) and benzaldehyde(3.5 g), 4-dimethylamino-2-(4-methylphenyl)-1-phenyl-2-buten-1-ol (Z)hydrochloride (2.3 g) is obtained, after recrystallisation from ethanol,in the form of white crystals melting at 185° C.

4-Methylacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone can beprepared as follows: 4-methylacetophenone (15.4 g) is added to asolution of 2,4,6-triisopropylbenzenesulphonylhydrazide (29.8 g) inmethanol (60 cc) containing a 3N solution (37 cc) of hydrochloric acidgas in ethyl ether. The reaction mixture is kept at a temperature in theregion of 5° C. for 18 hours, and is then filtered. The crystalsobtained are added to a mixture of methylene chloride (300 cc) and asaturated aqueous solution of sodium bicarbonate. The organic phase isseparated, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 40° C.4-Methylacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (21 g)is obtained, after recrystallisation from ethanol, in the form of whitecrystals melting at 202° C.

EXAMPLE 9

A 1.5M solution (134 cc) of n-butyllithium in hexane is added at atemperature in the region of -75° C. to a solution of acetophenone2,4,6-triisopropylbenzenesulphonylhydrazone (36.1 g) in1,2,-dimethoxyethane (1000 cc) kept under a nitrogen atmosphere.N,N-Dimethylmethyleneammonium iodide (18.5 g) is added to the orangesolution obtained; the suspension obtained is stirred vigorously for 20minutes at a temperature in the region of -50° C. A 1.5M solution (67cc) of n-butyllithium in hexane is then added at a temperature in theregion of -75° C., and the temperature is then allowed to rise slowly toapproximately 0° C.

The reaction mixture is then cooled to a temperature in the region of-30° C.; 3-pyridinecarboxaldehyde (10.7 g) dissolved in1,2-dimethoxyethane (50 cc) is then added and left stirred for 2 hoursat a temperature in the region of 20° C. A mixure of ethyl ether (500cc), an aqueous solution of concentrated hydrochloric acid (100 cc) anddistilled water (400 cc) is added. The aqueous phase is separated; theorganic phase is extracted with a 1N aqueous solution of hydrochloricacid (50 cc). The aqueous phases are combined, made alkaline to a pH inthe region of 11 with a 10N aqueous solution of sodium hydroxide andextracted with ethyl acetate (3×100 cc). The organic phases arecombined, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa) at 40° C. The residue obtainedis dissolved in ethanol (100 cc). Oxalic acid (7.7 g) is added to thesolution obtained; the crystals which appear are separated off byfiltration. After recrystallisation from methanol,4-dimethylamino-2-phenyl-1-(3-pyridyl)-2 -buten-1-ol (Z) sesquioxalate(14.8 g) is obtained in the form of a white powder melting at 195° C.

EXAMPLE 10

By using a method similar to that described in Example 9, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.2 g) and 2-pyridylcarboxaldehyde(3.6 g), 4-dimethylamino-2-phenyl-1-(2-pyridyl)-2-buten-1-ol (Z)sesquioxalate (4.4 g) is obtained, after recrystallisation from ethanol,in the form of white crystals melting at 152° C.

EXAMPLE 11

By using a method similar to that described in Example 9, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and4-pyridinecarboxyaldehyde (3.6 g),4-dimethylamino-2-phenyl-1-(4-pyridyl)-2-buten-1-ol (Z) oxalate (2.5 g)(2.5 moles of oxalic acid per mole of product) is obtained, afterrecrystallisation from acetone, in the form of yellow crystals meltingat 158° C.

EXAMPLE 12

By using a method similar to that described in Example 9, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and 4-methoxybenzaldehyde(4.5 g), 4-dimethylamino-1-(4-methoxyphenyl)-2-phenyl-2-buten-1-ol (Z)acid oxalate (3.5 g) is obtained, after recrystallisation from acetone,in the form of white crystals melting at 110° C.

EXAMPLE 13

By using a method similar to that described in Example 9, but startingfrom 4-methoxyacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(12.9 g), N,N-dimethylmethyleneammonium iodide (6.1 g) and benzaldehyde(3.5 g), 4-dimethylamino-2-(4-methoxyphenyl)-1-phenyl-2-buten-1-ol (Z)acid oxalate (1.6 g) is obtained, after recrystallisation from acetone,in the form of white crystals melting at 98° C.

4-Methoxyacetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone can beprepared by a method similar to that described in Example 8 for thepreparation of 4-methylacetophenone2,4,6-triisopropylbenzenesulphonylhydrazone. By starting from2,4,6-triisopropylbenzenesulphonylhydrazine (29.8 g) and4-methoxyacetophenone (15 g), 4-methoxyacetophenone2,4,6-triisopropylbenzenesulphonylhydrazone (28 g) is obtained, afterrecrystallisation from ethanol, in the form of white crystals melting at210° C.

EXAMPLE 14

By using a method similar to that described in Example 9, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and 4-fluorobenzaldehyde(4.1 g), 4-dimethylamino-1-(4-fluorophenyl)-2-phenyl-2-buten-1-ol (Z)acid oxalate (2 g) is obtained, after recrystallisation from acetone, inthe form of white crystals melting at 125° C.

EXAMPLE 15

By using a method similar to that described in Example 9, but startingfrom acetophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (12 g),N,N-dimethylmethyleneammonium iodide (6.1 g) and2-chloro-6-fluorobenzaldehyde (5.5 g),1-(2-chloro-6-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)acid oxalate (2.2 g) is obtained, after recrystallisation from acetone,in the form of white crystals melting at 88° C.

EXAMPLE 16

A solution of ethyl ether (10 cc) and of a 1.5N solution (6.4 cc) ofn-butyllithium in hexane is added to a solution of3-bromo-3-phenyl-1-dimethylamino-2-propene (Z) (2.3 g) in ethyl ether(40 cc) kept under a nitrogen atmosphere at a temperature in the regionof -78° C. and is left stirred for 15 minutes. A solution ofbenzaldehyde (1 cc) in 1,2-dimethoxyethane (10 cc) is added to the brownsolution obtained and stirring is continued at a temperature in theregion of 31 10° C. for 2 hours. The reaction mixture is then pouredinto distilled water (50 cc), adjusted to pH 2 with an aqueous solutionof concentrated hydrochloric acid. The aqueous phase is separated, madealkaline to pH 10 by addition of a 10N aqueous solution of sodiumhydroxide and then extracted with ethyl ether (2×200 cc). The organicphases are dried over sodium sulphate, filtered and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. The light yellow oilobtained is purified by "flash" chromatography [eluent: ethylacetate/methanol (50/50 by volume)]. After fractions 38 to 53 have beenevaporated to dryness under reduced pressure (2.7 kPa) at 40° C., aresidue obtained which is dissolved in ethanol (1 cc) and ethyl ether(0.3 cc). A 3.5N solution (0.7 cc) of hydrochloric acid gas in ethylether is added to the solution obtained. A solid precipitates; it isseparated off by filtration. In this way4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (0.3 g) isobtained in the form of a white powder melting at 172°-174° C.

3-Bromo-3-phenyl-1-dimethylamino-2-propene (Z) can be prepared asfollows: a solution of phosphorus oxybromide (54.2 g) in methylenechloride (45 cc) is added at a temperature in the region of 10° C. to asolution of dimethylaminoacrylophenone (33.1 g) in methylene chloride(120 cc) and is left stirred for 45 minutes at a temperature in theregion of 10° C. and then 30 minutes at ambient temperature. Methanol(150 cc) is then added at a temperature in the region of 0° C. After 10minutes, sodium cyanoborohydride (7.15 g) is added and stirring iscontinued for 3 hours at ambient temperature. The reaction mixture isevaporated to dryness under reduced pressure (2.7 kPa) at 30° C.; anorange oil is thus obtained, while is taken up in methylene chloride;the solution is filtered and then poured into iced water (200 cc). Afterbeing made alkaline to pH 10 by adding a 10N aqueous solution of sodiumhydroxide, the organic phase is separated, dried over sodium sulphate,filtered and evaporated to dryness under reduced pressure (2.7 kPa) at30° C. A red oil is obtained, which is dissolved in a mixture of ethanol(50 cc) and ethyl ether (75 cc); a 3.5N solution (60 cc) of hydrochloricacid gas in ethyl ether is added to the solution obtained. The solidformed is separated off by filtration and then recrystallised fromacetone (720 cc). 3-Bromo-3-phenyl-1-dimethylamino-2-propene (Z) (15.3g) is thus obtained in the form of a white powder melting at 174° C.

Dimethylaminoacrylophenone can be prepared by the method described by H.Meerwein, W. Florian, N. Schor, G. Stopp, Ann. Chem. 641, 1, (1961).

EXAMPLE 17

By using a method similar to that described in Example 16, but startingfrom 3-bromo-3-(4-chlorophenyl)-1-dimethylamino-2-propene (Z) (21.4 g),a 1.5N solution (56 cc) of n-butyllithium in hexane, and benzaldehyde(9.8 cc), and after purification by "flash" chromatography "eluent:methylene chloride/methanol (95/5 by volume)] and concentratingfractions 30 to 54 to dryness under reduced pressure (2.7 kPa) at 40°C., a residue is obtained which is dissolved in ethanol (10 cc). A 3.5Nsolution (5 cc) of hydrochloric acid gas in diethyl ether is added tothe solution obtained. The solid which precipitates is separated off byfiltration and then recrystallised from ethanol.2-(4-Chlorophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z)hydrochloride (3 g) is thus obtained in the form of a white powdermelting at 172° C.

3-Bromo-3-(4-chlorophenyl)-1-dimethylamino-2-propene (Z) can be preparedby a method similar to that described in Example 16, but starting from1-(4-chlorophenyl)-3-dimethylamino-2-buten-1-one, phosphorus oxybromide(61.3 g) and sodium cyanoborohydride (8.10 g). Evaporation to drynessunder reduced pressure (2.7 kPa) at 30° C. of the reaction mixtureproduces a yellow solid which is taken up in chloroform. The solution isfiltered and the filtrate is evaporated under reduced pressure (2.7 kPa)at 30° C. The solid obtained is washed with a methanol/ethyl ethermixture (75/25 by volume). In this way3-bromo-3-(4-chlorophenyl)-1-dimethylamino-2-propene (Z) hydrobromide(45.9 g) is obtained in the form of a white solid melting at 174° C.

1-(4-Chlorophenyl)-3-dimethylamino-2-buten-1-one can be prepared by themethod described by Yang-I-Lin and S. A. Lang, Jr., J. Org. Chem., 45,4857, (1980).

EXAMPLE 18

By using a method similar to that described in Example 16, but startingfrom 3-bromo-3-(4-chlorophenyl)-1-dimethylamino-2-propene (Z) (10 g), a1.5N solution (26 cc) of n-butyllithium in hexane and3-pyridinecarboxaldehyde (4.20 g), an oil is obtained, which is purifiedby "flash" chromatography [eluent: methylene chloride/methanol (90/10 byvolume)]. After fractions 19 to 50 have been evaporated to dryness underreduced pressure (2.7 kPa) at 40° C., a residue is obtained which isdissolved in ethanol (25 cc). A 1.7M ethanolic solution (13 cc) ofoxalic acid is added to the solution obtained; the precipitate which isformed is separated off by filtration and then recrystallised frommethanol (36 cc) and distilled water (4 cc) . In this way2-(4-chlorophenyl)-4-dimethylamino-1-(3-pyridyl)-2-buten-1-ol (Z)sesquioxalate (3.5 g) is obtained in the form of white crystals meltingat 187° C.

EXAMPLE 19

By using a method similar to that described in Example 16, but startingfrom 3-bromo-3-(4-fluorophenyl)-1-dimethylaminopropene (Z) (20 g), a1.5N solution (57 cc) of n-butyllithium in hexane, and benzaldehyde (10cc), an oil is obtained which is purified by "flash" chromatography[eluent: methylene chloride/methanol (90/10 by volume)]. After fractions36 to 79 have been evaporated to dryness under reduced pressure (2.7kPa) at 40° C., a residue is obtained which is disssolved inacetonitrile (20 cc) and ethyl ether (60 cc). A 3N solution (5.6 cc) ofhydrochloric acid gas in ethyl ether is added to the solution obtained.The precipitate which is formed is separated off by filtration and theyrecrystallised from isopropanol (15 cc). In this way4-dimethylamino-2-(4-fluorophenyl)-1-phenyl)-2-buten-1-ol (Z)hydrochloride (2 g) is obtained in the form of white crystals melting at141° C.

3-Bromo-3-(4-fluorophenyl)-1-dimethylamino-2-propene (Z) can be preparedby a method similar to that described in Example 16, but starting from1-(4-fluorophenyl)-3-dimethylamino-2-buten-1-one (26.5 g), phosphorusoxybromide (39.15 g) and sodium cyanoborohydride (5.15 g). Evaporationof the reaction mixture to dryness under reduced pressure (2.7 kPa) at30° C. produces a yellow solid which is taken up in chloroform. Afterfiltration, the chloroform phase is evaporated under reduced pressure(2.7 kPa) at 30° C. to give a solid which is crystllised from methanol(50 cc) and ethyl ether (25 cc). In this way3-bromo-3-(4-fluorophenyl)-1-dimethylamino-2-propene (Z) hydrobromide(30 g) is obtained in the form of a white solid melting at approximately156° C.

1-(4-Fluorophenyl)-3-dimethylamino-2-buten-1-one can be prepared by themethod described by J. D. Albright et al., U.S. Pat. No. 4,209,621.

EXAMPLE 20

By using a method similar to that described in Example 16, but startingfrom 3-bromo-3-phenyl-1-(N-piperidino)-2-propene (Z) (13.6 g), a 1.5Nsolution (36 cc) of n-butyllithium in hexane, and benzaldehyde (6.5 cc),and after a 1N aqueous solution (50 cc) of hydrochloric acid has beenadded to the reaction mixture at 0° C., a white precipitate is obtained.After the precipitate has been separated off by filtration and washedwith ethyl ether, and solid obtained is taken up in methylene chloride.The organic phase is dried over sodium sulphate, filtered and evaporatedto dryness under reduced pressure (2.7 kPa) at 30° C., to give a residuewhich is recrystallised from isopropanol (80 cc). In this way1,2-diphenyl-4-(N-piperidino)-2-buten-1-ol (Z) hydrochloride (2.7 g) isobtained in the form of white crystals melting at 195°-196° C.

3-Bromo-3-phenyl-1-(N-piperidino)-2-propene (Z) can be prepared by amethod similar to that described in Example 16, but starting from3-N-piperidinoacrylophenone (29.1 g), phosphorus oxybromide (38.8 g) andsodium cyanoborohydride (5.1 g). Evaporation of the reaction mixture todryness under reduced pressure (2.7 kPa) at 30° C. produces a yellowsolid which is taken up in chloroform. After filtration, the chloroformphase is concentrated under reduced pressure (2.7 kPa) at 30° C. to givea yellow solid which is crystallised from isopropanol. In this way3-bromo-3-phenyl-1-(N-piperidino)-2-propene (Z) hydrobromide (26.5 g) isobtained in the form of a white solid melting at 204°-205° C.

3-N-Piperidinoacrylophenone can be prepared by a method similar to thatdescribed by E. Benary, Ber, 63, 1573 (1930).

EXAMPLE 21

By using a method similar to that described in Example 16, but startingfrom 3-bromo-3-(4-bromophenyl)-1-dimethylamino-2-propene (Z) (21 g), a1.5N solution (48 cc) of n-butyllithium in hexane, and benzaldehyde (8.5cc), an oil is obtained which is purified by "flash" chromatography[eluent: dichloromethane/methanol (93/7 by volume)]. After fractions 25to 39 have been evaporated to dryness under reduced pressure (2.7 kPa)at 40° C., a residue is obtained, which is dissolved in acetonitrile (40cc). A 3N solution (9.7 cc) of hydrochloric acid gas in ethyl ether isadded to the solution obtained; the solid which is formed is separatedoff by filtration and then recrystallised from acetonitrile (100 cc). Inthis way 2-(4-bromophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z)hydrochloride (5.2 g) is obtained in the form of a white solid meltingat 178° C.

3-Bromo-3-(4-bromophenyl)-1-dimethylamino-2-propene (Z) can be preparedby a method similar to that described in Example 16, but starting from1-(4-bromophenyl)-3-dimethylamino-2-propen-1-one (38 g), phosphorusoxybromide (42.9 g) and sodium cyanoborohydride (5.68 g). Evaporation ofthe reaction mixture to dryness under reduced pressure (2.7 kPa) at 30°C. produces a yellow solid which is crystallised from methanol. In thisway, 3-bromo-3-(4-bromophenyl)-1-dimethylamino-2-propene (Z)hydrobromide (28 g) is obtained in the form of a white solid melting at180° C.

1-(4-Bromophenyl)-3-dimethylamino-2-propen-1-one can be prepared by amethod similar to that described by Yang-I-Lin and S. A. Lang Jr., J.Org. Chem., 45, 4857, (1980).

EXAMPLE 22

A 1.5M solution (29 cc) of n-butyllithium in hexane is added to asolution of β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (9.15 g) in1,2-dimethoxyethane (100 cc) kept under a nitrogen atmosphere at atemperature in the region of -75° C. The orange solution obtained isthen stirred for 15 minutes at a temperature in the region of 0° C., andthen cooled to a temperature in the region of -40° C. Benzaldehyde (2.2cc) is then added, and then the reaction mixture is stirred for 1 hourat a temperature in the region of 20° C. A 1N aqueous solution (100 cc)of hydrochloric acid is then added with stirring, followed by ethylether (100 cc). The aqueous phase is separated; the organic phase isextracted with a 0.1N aqueous solution (25 cc) of hydrochloric acid. Theaqueous phases are combined, washed with ether (2×50 cc) and then madealkaline to a pH in the region of 10 with sodium hydroxide solution, andthen extracted with ethyl acetate (3×50 cc). The organic phases arecombined, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 40° C. In this way4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) (5.2 g) is obtained in theform of white crystals melting at 75° C.

β-Dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazonecan be prepared as follows: β-dimethylaminopropiophenone hydrochloride(77.3 g), followed by distilled water (33 cc) are added to a suspensionof 2,4,6-triisopropylbenzenesulphonylhydrazine in a mixture of methanol(130 cc) and a 3N solution (130 cc) of hydrochloric acid gas in ethylether, and the reaction mixture is stirred at a temperature in theregion of 20° C. for 20 hours. The reaction mixture is cooled to atemperature in the region of +5° C.; the crystals formed are separatedoff by filtration and then added to a mixture of methylene chloride (550cc), a 4N aqueous solution (110 cc) of sodium hydroxide and distilledwater (275 cc), and the mixture is stirred vigorously. The organic phaseis then separated; the aqueous phase is extracted with methylenechloride (3×150 cc). The organic phases are combined, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. The residue obtained iscrystallised from isopropanol; in this way β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (79 g) is obtained in theform of a white powder melting at 164° C.

EXAMPLE 23

By using a method similar to that described in Example 22, but startingfrom β-diethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (30 g) and benzaldehyde (6.9cc), 4-diethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (3.2 g)is obtained, after recrystallisation from acetone, in the form of whitecrystals melting at 140° C.

β-Diethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazonecan be prepared by a method similar to that described in Example 22 forthe preparation of β-diethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone but starting from2,4,6-triisopropylbenzenesulphonylhydrazine (51.8 g) andβ-diethylaminopropiophenone hydrochloride (64.4 g). In this wayβ-diethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(53.6 g) is obtained in the form of cream crystals melting at 134° C.

β-Diethylaminopropiophenone hydrochloride can be prepared by the methoddescribed by C. E. Maxwell, Org. Synth. Coll. Vol. III, John Wiley &Sons, London (1955) page 305.

EXAMPLE 24

By using a method similar to that described in Example 22, but startingfrom β-(1-pyrrolidinyl)propiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g), and benzaldehyde(4.6 cc), 1,2-diphenyl-4-(1-pyrrolidinyl)-2-buten-1-ol (Z) hydrochloride(9.9 g) is obtained, after recrystallisation from a mixture of2-propanol and isopropyl ether (40/60 by volume), in the form of whitecrystals melting at 106° C.

β-(1-Pyrrolidinyl)propiophenone2,4,6-triisopropylbenzenesulphonylhydrazone can be prepared by a methodsimilar to that described in Example 22 for the preparation ofβ-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone, but starting from2,4,6-triisopropylbenzenesulphonylhydrazine (17.9 g) andβ-(1-pyrrolidinyl)propiophenone hydrochloride (14.4 g). In this wayβ-(1-pyrrolidinyl)propiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) is obtained in theform of white crystals melting at 142° C.

β-(1-Pyrrolidinyl)propiophenone hydrochloride can be prepared by amethod similar to that described by C. E. Maxwell, Org. Synth., coll.Vol III, John Wiley & Sons, London (1955) page 305, but starting frompyrrolidine hydrochloride (58.8 g) acetophenone (60.1 g) andpolyoxymethylene (22.5 g). In this way β-(1-pyrrolidinyl)propiophenonehydrochloride (66 g) is obtained in the form of white crystals meltingat 164° C.

EXAMPLE 25

By proceeding as in Example 22 but starting fromβ-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(18.9 g), a 1.5M solution (61 cc) of n-butyllithium and3-chlorobenzaldehyde (6.4 g) in 1,2-dimethoxyethane (190 cc) and afterrecrystallising from isopropanol (125 cc),1-(3-chloropheny)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)hydrochloride (8.9 g) is obtained, melting at 185° C.

EXAMPLE 26

By proceeding as in Example 22 but starting fromβ-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(15 g), a 1.5M solution (48 cc) of n-butyllithium in hexane, and3-fluorobenzaldehyde (4.5 g), in 1,2-dimethoxyethane (150 cc), and afterrecrystallising from a mixture (215 cc) of acetone and isopropanol (93/7by volume), 1-(3-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)hydrochloride (5.3 g), melting at 165° C., is obtained.

EXAMPLE 27

By proceeding as in Example 22 but starting fromβ-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(20 g), a 1.5M solution (64 cc) of n-butyllithium in hexane, and2-chlorobenzaldehyde (6.8 g), in 1,2-dimethoxyethane (200 cc), and afterrecrystallising the crude product in the base form from a mixture (62cc) of isopropyl ether and petroleum ether (50/50 by volume),1-(2-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z) (5.2 g),melting at 90° C. is obtained.

EXAMPLE 28

By proceeding as in Example 22 but starting fromβ-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(20 g), a 1.5M solution (64 cc) of n-butyllithium in hexane, and3-methoxybenzaldehyde (6.5 g) in 1,2-dimethoxyethane (200 cc), and afterrecrystallising the crude product in the base form from acetone (200cc), 1-(3-methoxyphenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z) (4.7g), melting at 160° C., is obtained.

EXAMPLE 29

By proceeding as in Example 22 but starting fromβ-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone(20 g), a 1.5M solution (65 cc) of n-butyllithium in hexane and2,3-dimethoxybenzaldehyde (8 g), in 1,2-dimethoxyethane (200 cc), andafter recrystallising the crude product in the base form from isopropylether (100 cc),1-(2,3-dimethoxyphenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z) (6.7g), melting at 105° C., is obtained.

EXAMPLE 30

Sodium borohydride (10.3 g) is added over approximately 30 minutes at atemperature in the region of 5° C. to a solution of2,3-diphenyl-5-methylamino-2,5-dihydrofuran (9.7 g) in methanol (90 cc)and distilled water (10 cc). The reaction mixture is then stirred for 18hours at a temperature in the region of 20° C., and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. The residue obtainedis triturated with methylene chloride (100 cc); the suspension obtainedis filtered and the filtrate is concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. The residue is purified by chromatographyon silica gel (400 g) in a 4 cm diameter column [eluent:methanol/aqueous ammonia (98/2 by volume)]. Elution is first carried outwith solvent (400 cc); the corresponding eluate is discarded; elutionthen continues with solvent (600 cc); the corresponding eluate isconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Theresidue obtained is recrystallised from a mixture of hexane (70 cc) andisopropanol (10 cc). In this way 1,2-diphenyl-4-methylamino-2-buten-1-ol(Z) (3.8 g) is obtained in the form of white crystals melting at 90° C.

2,3-Diphenyl-5-methylamino-2,5-dihydrofuran can be prepared as follows:benzoin (29.7 g) dissolved in tetrahydrofuran (400 cc) is added to asuspension of sodium hydride (3.4 g) in tetrahydrofuran (50 cc) keptunder a nitrogen atmosphere at a temperature in the region of 0° C., andthe reaction mixture is stirred for 30 minutes while the temperature isallowed to return to 20° C. Diethyl 2-methyliminoethylphosphonate (27 g)in tetrahydrofuran (270 cc) is then added. The reaction mixture is thenheated to reflux for 1 hour and then cooled to a temperature in theregion of 20° C. Water (1 liter) is then added and the mixture isextracted twice with ethyl acetate (200 cc in total). The organic phaseis washed with water (2×100 cc) and then dried over magnesium sulphate,filtered and then evaporated to dryness under reduced pressure (2.7 kPa)at 40° C. The residue is washed with ethyl ether (100 cc) and thenfiltered. The filtrate is evaporated to dryness under reduced pressure(2.7 kPa) at 40° C. to give an oil which is purified by "flash"chromatography [eluent: ethyl acetate]. After fractions 8 and 19 havebeen evaporated to dryness under reduced pressure (2.7 kPa) at 40° C.,an orange oil is obtained which is dissolved in a mixture (20 cc) ofethyl acetate and ethyl ether (50/50 by volume). A 5.7N solution (3.9cc) of hydrochloric acid gas in ethyl ether is added to the solution.The solid obtained is separated off by filtration and thenrecrystallised from isopropanol (120 cc). In this way2,3-diphenyl-5-methylamino-2,5-dihydrofuran hydrochloride (2.8 g) isobtained in the form of a white solid melting at 190° C.

Diethyl 2-methyliminoethylphosphonate can be prepared as follows: a 33%solution (16.5 cc) of methylamine is added to a solution ofdiethylphosphonoacetaldehyde (32.4 g) in methanol (100 cc). The reactionmixture is stirred for 3 hours at a temperature in the region of 20° C.,and is then concentrated to dryness under reduced pressure (2.7 kPa) at40° C. The residue is dissolved in the minimum quantity of ethyl ether;the solution obtained is dried over potassium carbonate, filtered andthen concentrated to one third of the original volume under reducedpressure (2.7 kPa) at 20° C. The crystals obtained are separated off byfiltration and then dried at a temperature in the region of 20° C. Inthis way diethyl 2-methyliminoethylphosphonate (18.4 g) is obtained inthe form of a yellow powder melting at 66° C.

Diethylphosphonoacetaldehyde can be prepared by the method described byN. D. Dawson and A. Burger, J. Am. Chem. Soc., 74, 5312, (1952).

EXAMPLE 31

By using a method similar to that described in Example 30, but startingfrom 2,3-diphenyl-5-ethylamino-2,5-dihydrofuran (25 g) and sodiumborohydride (25 g), and after purification by chromatography on silicagel (eluent: methanol) followed by recrystallisation from isopropylether, 1,2-diphenyl-4-ethylamino-2-buten-1-ol (Z) (8.4 g) is obtained inthe form of a white powder melting at 82° C.

2,3-Diphenyl-5-ethylamino-2,5-dihydrofuran can be prepared by a methodsimilar to that described in Example 30, but starting from diethyl2-ethyliminoethylphosphonate (63 g), benzoin (64 g) and sodium hydride(6.55 g). An oil is obtained, which is purified by chromatography onsilica gel [eluent: ethyl acetate/cyclohexane (50/50 by volume)]. Inthis way 2,3-diphenyl-5-ethylamino-2,5-dihydrofuran (25 g) is obtainedin the form of an orange-yellow oil [R_(f) =0.4; chromatography onsilica gel; eluent: ethyl acetate/cyclohexane (50/50 by volume)].

Diethyl 2-ethyliminoethylphosphonate can be prepared by a method similarto that described in Example 30, but starting fromdiethylphosphonoacetaldehyde (60 g) and ethylamine (15 g). After thereaction mixture has been concentrated to dryness under reduced pressure(2.7 kPa) at 40° C., diethyl 2-ethyliminoethylphosphonate (63.8 g) isobtained in the form of a yellow oil [R_(f) =0.47; chromatography onsilica gel; eluent: ethyl acetate/ methanol (92.5/7.5 by volume)].

EXAMPLE 32

By using a method similar to that described in Example 30, but startingfrom 2,3-diphenyl-5-(2-propylamino)-2,5-dihydrofuran (33.3 g) and sodiumborohydride (31.6 g), 1,2-diphenyl-4-(2-propylamino)-2-buten-1-ol (Z)hydrochloride (9.4 g) is obtained, in the form of white crystals meltingat 188° C., after conversion to the hydrochloride in ethyl ether andrecrystallization of this hydrochloride from ethanol.

2,3-Diphenyl-5-(2-propylamino)-2,5-dihydrofuran can be prepared by amethod similar to that described in Example 30, but starting fromdiethyl 2-(2-propylamino)ethylphosphonate (66 g), benzoin (63.3 g) andsodium hydride (12.9 g). In this way2,3-diphenyl-5-(2-propylamino)-2,5-dihydrofuran (33.3 g) is obtained inthe form of a yellow oil [R_(f) =0.46; thin layer chromatography onsilica gel, eluent: ethyl acetate/cyclohexane (50/50 by volume)].

Diethyl 2-(2-propylimino)ethylphosphonate can be prepared by a methodsimilar to that described in Example 30, but starting fromdiethylphosphonoacetaldehyde (60 g) and isopropylamine (19.7 g). In thisway diethyl 2-(2-propylimino)ethylphosphonate (67.9 g) is obtained inthe form of a yellow oil [R_(f) =0.53; thin layer chromatography onsilica gel, eluent: ethyl acetate/methanol (92.5/7.5 by volume)].

EXAMPLE 33

By using a method similar to that described in Example 30, but startingfrom 5-butylamino-2,3-diphenyl-2,5-dihydrofuran (29.6 g) and sodiumborohydride (26.7 g), and after conversion to the hydrochloride in ethylether and recrystallisation of this hydrochloride from acetone,4-butylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (4.3 g) isobtained in the form of white crystals melting at 155° C.

5-Butylamino-2,3-diphenyl-2,5-dihydrofuran can be prepared by a methodsimilar to that described in Example 30, but starting from diethyl2-butyliminoethylphosphonate (64 g), benzoin (57.7 g) and sodium hydride(11.8 g); in this way, 5-butylamino-2,3-diphenyl-2,5-dihydrofuran (29.6g) is obtained in the form of an orange oil [R_(f) =0.50; thin layerchromatography on silica gel, eluent: ethyl acetate/cyclohexane (50/50by volume)].

Diethyl 2-butyliminoethylphosphonate can be prepared by a method similarto that described in Example 30 but starting fromdiethylphosphonoacetaldehyde (54 g) and butylamine (21.9 g). In this waydiethyl 2-butyliminoethylphosphonate (66.2 g) is obtained in the form ofa yellow oil [R_(f) =0.40; thin layer chromatography on silica gel,eluent: ethyl acetate/methanol (92.5/7.5 by volume)].

EXAMPLE 34

By using a method similar to that described in Example 30, but startingfrom 5-allylamino-2,3-diphenyl-2,5-dihydrofuran (26.9 g) and sodiumborohydride (25 g), a crude product is obtained which is purified bychromatography on silica gel (100 g) in an 8 cm diameter column (eluent:methanol). The yellow oil obtained (6 g) is dissolved in ethyl ether(100 cc).

A 3.5N solution (20 cc) of hydrochloric acid gas in ethyl ether is addedto the solution obtained. The crystals which precipitate are separatedoff by filtration and recrystallised from a mixture of isopropyl etherand acetone (50/50 by volume). In this way4-allylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (4.2 g) isobtained in the form of a white powder melting at 113° C.

5-Allylamino-2,3-diphenyl-2,5-dihydrofuran can be prepared by a methodsimilar to that described in Example 30 for the synthesis of2,3-diphenyl-5-methylamino-2,5-dihydrofuran, but starting from diethyl2-allyliminoethylphosphonate (32.3 g), benzoin (31.3 g) and sodiumhydride (3.2 g). In this way 5-allylamino-2,3-diphenyl-2,5-dihydrofuran(26.9 g) is obtained in the form of a yellow oil [R_(f) =0.5; thin layerchromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50by volume)].

Diethyl 2-allyliminoethylphosphonate can be prepared by a method similarto that described in Example 30 for the preparation of diethyl2-methyliminoethylphosphonate; but starting fromdiethylphosphonoacetaldehyde (29 g) and allylamine (11.8 cc). Diethyl2-allyliminoethylphosphonate (32.3 g) is obtained in the form of ayellow oil [R_(f) =0.38; thin layer chromatography on silica gel;eluent: ethyl acetate/methanol (92.5/7.5 by volume)].

EXAMPLE 35

Phosphorus oxychloride (2.5 cc) dissolved in methylene chloride (6 cc)is added dropwise at 0° C. to a solution of 3-dimethylaminoacrylophenone(5 g) in methylene chloride (16 cc). After stirring for 15 minutes at 0°C. and then 30 minutes at 20° C., the temperature is again brought downto 0° C. The precipitate formed is dissolved by adding methanol (5 cc).Triethylamine (8 cc) and thiophenol (3.15 cc) dissolved in methylenechloride (10 cc) are added dropwise. After 2 hours 30 minutes' stirringat 20° C., methanol (30 cc) is added followed by sodium cyanoborohydride(1 g) at 0° C. and stirring is continued for 3 hours at 20° C. Themixture is then concentrated under reduced pressure (2.7 kPa) at 40° C.The solid obtained is taken up in chloroform and the solution isfiltered. The organic phase is evaporated under reduced pressure (2.7kPa) at 40° C. The residue obtained is taken up in water and thesolution is made alkaline to pH 10 by adding a 35% strength aqueoussolution of sodium hydroxide, and then extracted with methylenechloride. The organic phase is dried over sodium sulphate, filtered andthen evaporated to dryness under reduced pressure (2.7 kPa) at 40° C.The residue obtained is dissolved in ethyl ether (10 cc). A 3N solution(10 cc) of hydrochloric acid gas in ethyl ether is added to the solutionobtained. The precipitate formed is separated off by filtration and thenrecrystallised from a mixture of ethanol (15 cc) and ethyl ether (20cc). In this way 1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z)hydrochloride (3 g) is obtained in the form of white crystals melting at176° C.

3-Dimethylaminoacrylophenone can be prepared by the method described byH. Meerwein, W. Florian, N. Schon and G. Stopp, Ann. Chem. 641, 1,(1961).

EXAMPLE 36

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (80 g), phosphorus oxychloride (40cc), thiophenol (50.3 cc) and sodium cyanoborohydride (16 g), andcrystallising the (Z)-isomer, a yellow solid is isolated afterevaporation of the mother liquors under reduced pressure (2.7 kPa) at30° C. followed by crystallisation of the residue obtained from amixture of acetone and ethyl ether (25/75 by volume); the solid isrecrystallised from methyl ethyl ketone (230 cc).1-Dimethylamino-3-phenyl-3-phenylthio-2-propene (E) hydrochloride (14.3g) is thus obtained in the form of a white solid melting at 146°-147° C.

EXAMPLE 37

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.5cc), p-chlorothiophenol (4.13 g) and sodium cyanoborohydride (1 g), andafter evaporating the reaction mixture under reduced pressure (2.7 kPa)at 40° C., a residue is obtained, which is dissolved in ethanol (50 cc).A 3N solution (12 cc) of hydrochloric acid gas in ethyl ether is addedto this solution. The precipitate formed is separated off by filtrationand then recrystallised from ethanol (70 cc). In this way3-(4-chlorophenylthio)-1-dimethylamino-3-phenylthio-2-propene (Z)hydrochloride (3.4 g) is obtained in the form of a white powder meltingat 226° C.

EXAMPLE 38

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (10 g), phosphorus oxychloride (5 cc),4-mercaptopyridine (6.35 g) and sodium cyanoborohydride (2 g), achestnut-coloured residue is obtained which is taken up in water (100cc). The solution is acidified to pH 2 by adding an aqueous solution ofconcentrated hydrochloric acid and then washed with ethyl ether (2×50cc). The aqueous phase is adjusted to pH 10 by adding a concentratedaqueous solution of sodium hydroxide and then extracted with methylenechloride. The resultant organic phase is dried over sodium sulphate,filtered and then concentrated to dryness under reduced pressure (2.7kPa) at 30° C. to give a red residue which is chromatographed on silicagel [eluent: methylene chloride/methanol (95/5 by volume)], 200 ccfractions being collected. Fractions 13 to 25 are concentrated underreduced pressure (2.7 kPa) at 30° C. A residue is obtained which isdissolved in ethanol (15 cc). A 1.2N ethanolic solution (20 cc) ofoxalic acid is added to this solution; the solid which precipitates isseparated off by filtration and recrystallised from a mixture (110 cc)of acetonitrile and ethanol (20/80 by volume). In this way1-dimethylamino-3-phenyl-3-(4-pyridylthio)-2-propene (Z) sesquioxalate(3 g) is obtained in the form of white crystals melting at 173° C.

EXAMPLE 39

By using a method similar to that described in Example 35, but startingfrom 1-(4-chlorophenyl)-3-dimethylamino-2-propen-1-one (10 g),phosphorus oxychloride (4.2 cc), thiophenol (5.2 cc) and sodiumcyanoborohydride (1.79 g), an orange residue is obtained which is takenup in water (100 cc). The solution is made alkaline to pH 10 by adding aconcentrated aqueous solution of sodium hydroxide and then extractedwith methylene chloride. The organic phase is dried over sodiumsulphate, filtered, and then evaporated to dryness under reducedpressure (2.7 kPa) at 30° C. The residue obtained is purified by "flash"chromatography [eluent: methylene chloride/methanol (95/5 by volume)].After fractions 33 to 60 have been evaporated to dryness under reducedpressure (2.7 kPa) at 30° C., a yellow oil (7.8 g) is obtained. This oilis dissolved in acetone (50 cc) and a 1.3M solution (20 cc) of oxalicacid in acetone is added to the solid obtained. The white solid whichprecipitates is separated off by filtration and recrystallised fromethanol (130 cc). In this way3-(4-chlorophenyl)-1-dimethylamino-3-phenylthio-2-propene (Z) acidoxalate (3 g) is obtained in the form of white crystals melting at 183°C.

1-(4-Chlorophenyl)-3-dimethylamino-2-propen-1-one can be obtained by themethod described by H. Meerwein, W. Florian, N. Schon and G. Stopp, Ann.Chem. 641, 1, (1961).

EXAMPLE 40

By using a method similar to that described in Example 35, but startingfrom 1-(4-fluorophenyl)-3-dimethylamino-2-propen-1-one (10 g),phosphorus oxychloride (4.76 cc), thiophenol (5.57 cc) and sodiumcyanoborohydride (1.92 g), a residue is obtained which is taken up inchloroform. The solution is then adjusted to pH 10 by adding aconcentrated aqueous solution of sodium hydroxide. The organic phase isseparated and then the aqueous phase is extracted with methylenechloride. The organic phases are collected, dried over sodium sulphate,filtered and then evaporated to dryness under reduced pressure (2.7 kPa)at 30° C. A residue is obtained which is dissolved in isopropanol (30cc). A 3N solution (12 cc) of hydrochloric acid gas in ethyl ether isadded to this solution. The solid which precipitates is separated off byfiltration and recrystallised from isopropanol (30 cc). In this way1-dimethylamino-3-(4-fluorophenyl)-3-phenylthio-2-propene (E)hydrochloride (3.3 g) is obtained in the form of a white solid meltingat 160° C.

1-(4-Fluorophenyl)-3-dimethylamino-2-propen-1-one can be obtained byusing the method described by H. Meerwein, W. Florian, N. Schon and G.Stopp, Ann. Chem. 641, 1, (1961).

EXAMPLE 41

By starting with the crystallisation mother liquors obtained in Example40 and evaporating the solvents, a residue is obtained which isdissolved in water (50 cc). The solution obtained is made alkaline to pH10 with a concentrated solution of sodium hydroxide. After extractionwith methylene chloride, the organic phase is dried over sodiumsulphate, filtered and evaporated to dryness. An orange oil is obtainedwhich is purified by "flash" chromatography [eluent: methylenechloride/methanol (95/5 by volume)]. Fractions 33 to 100 areconcentrated under reduced pressure (2.7 kPa) at 30° C. to give aresidue which is dissolved in ethanol (40 cc). A 1.1M solution (30 cc)of oxalic acid in acetone is added to this solution. The solid whichprecipitates is separated off by filtration and recrystallised fromethanol (40 cc). In this way1-dimethylamino-3-(4-fluorophenylthio)-3-phenyl-2-propene (Z) oxalate(2.5 g) is obtained in the form of a white solid melting at 163° C.

EXAMPLE 42

By using a method similar to that described in Example 35, but startingfrom 1-(4-bromophenyl)-3-dimethylamino-2-propen-1-one (10 g), phosphorusoxychloride (3.64 g), thiophenol (4.2 cc) and sodium cyanoborohydride(1.47 g), a residue is obtained which is taken up in chloroform. Thesolution is adjusted to pH 10 by adding a concentrated aqueous solutionof sodium hydroxide. The organic phase is separated and then the aqueousphase is extracted with methylene chloride. The organic phases arecollected, dried over sodium sulphate, filtered and then evaporated todryness under reduced pressure (2.6 kPa) at 30° C. to give a residuewhich is dissolved in isopropanol (30 cc). A 3N ether solution (13 cc)of hydrochloric acid gas is added to the solution obtained. The whitesolid which precipitates is separated off by filtration andrecrystallised twice from ispropanol (40 cc). In this way3-(4-bromophenyl)-1-dimethylamino-3-phenylthio-2-propene (E)hydrochloride (4.8 g) is obtained in the form of white crystals meltingat 187° C.

1-(4-Bromophenyl)-3-dimethylamino-2-propen-1-one can be obtained byusing the method of H. Meerwein, W. Florian, N. Schon and G. Stopp, Ann.Chem. 641, 1, (1961).

EXAMPLE 43

By starting with the crystallisation mother liquors obtained in Example42 and evaporating the solvents, a residue is obtained which isdissolved in water (100 cc). The solution obtained is made alkaline topH 10 by adding an aqueous solution of sodium hydroxide. Afterextraction with methylene chloride, the organic phase is dried oversodium sulphate, filtered and then concentrated under reduced pressure(2.7 kPa) at 30° C. A residue is obtained which is dissolved in ethanol(20 cc). A 1.7M solution (10 cc) of oxalic acid in acetone is added tothis solution. The white solid which precipitates is separated off byfiltration and recrystallised from ethanol (160 cc). In this way a 75/25mixture (3.7 g) of the oxalates of3-(4-bromophenyl)-1-dimethylamino-3-phenylthio-2-propene (Z) and of3-(4-bromophenyl)-1-dimethylamino-3-phenylthio-2-propene (E) is obtainedin the form of white crystals melting at 281° C.

EXAMPLE 44

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.47cc), 4-bromothiophenol (5.39 g) and sodium cyanoborohydride (1 g), achestnut-coloured residue is obtained which is taken up in chloroform.The solution is made alkaline to pH 10 with an aqueous solution ofsodium hydroxide. After separation of the chloroform phase, the aqueousphase is extracted with methylene chloride. The organic phases arecollected, dried over sodium sulphate, filtered and then evaporated todryness under reduced pressure (2.7 kPa) at 30° C. A residue is obtainedwhich is dissolved in ethanol (60 cc). A 3N ether solution (7.7 cc) ofhydrochloric acid gas is added to this solution. The white solid whichprecipitates is separated off by filtration and recrystallised from amixture of isopropanol and methanol (60/40 by volume). In this way3-(4-bromophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z)hydrochloride (1.8 g) is obtained in the form of a white solid meltingat 252° C.

EXAMPLE 45

Dimethylamine hydrochloride (139 g) and 3 Å molecular sieve (2 g) areadded to a stirred solution of 3-phenyl-3-phenylthio-2-propenal (Z)(40.5 g) in methanol (370 cc) under an argon atmosphere. After 5minutes' stirring, sodium cyanoborohydride (10.7 g) is added andstirring is continued for 18 hours. An aqueous solution (26 cc) ofconcentrated hydrochloric acid is then added and the mixture isconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Theresidue obtained is taken up in water and then washed with ethyl ether.The aqueous phase is made alkaline to pH 10 by adding a 35% strengthaqueous solution of sodium hydroxide and then taken up with methylenechloride. The organic phase is separated and filtered on diatomaceousearth, washed with water (100 cc) and then dried over sodium sulphate.After filtration, the organic phase is evaporated to dryness underreduced pressure (2.7 kPa) at 40° C. A chestnut-coloured oil is thusobtained, which is purified by chromatography on silica gel [eluent:methylene chloride/methanol (90/10 by volume)], 50-cc fractions beingcollected. After fractions 20 to 30 have been concentrated to dryness, aresidue is obtained which is dissolved in ethanol (10 cc) and ethylether (70 cc). A 3.5N solution (17 cc) of hydrochloric acid gas in ethylether is added to this solution. The precipitate formed is separated offby filtration and then recrystallised from a mixture of ethanol (38 cc)and ethyl ether (50 cc). In this way1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z) hydrochloride (8.9g) is obtained in the form of white crystals melting at 176° C.

3-Phenyl-3-phenylthio-2-propenal (Z) can be prepared as follows:triethylamine (9.66 cc) and then thiophenol (5.7 cc) are added at 0° C.to a solution of 3-chloro-3-phenyl-2-propenal (Z) (9.4 g) indichloromethane (50 cc). After 14 hours' stirring at 20° C., the mixtureis poured into water (50 cc); the solution is adjusted to pH 7 by addingan aqueous solution of concentrated hydrochloric acid and is then takenup with methylene chloride. The organic phase is separated, dried oversodium sulphate, filtered and then evaporated to dryness under reducedpressure (2.7 kPa) at 40° C. In this way a residue is obtained which ispurified by chromatography on silica gel [eluent: hexane followed byethyl acetate]; after elution of the nonpolar impurities with hexane(400 cc), fractions 8 to 15 produced by elution with ethyl acetate (400cc) are combined and evaporated to dryness under reduced pressure (2.7kPa) at 40° C. In this way 3-phenyl-3-phenylthio-2-propenal (Z) (7.8 g)is obtained in the form of a red oil with R_(f) =0.9 in thin layerchromatography on silica gel [eluant: ethyl acetate/hexane (50/50 byvolume)].

3-Chloro-3-phenyl-2-propenal (Z) can be prepared by the method describedby C. M. Beaton, N. B. Chapman and K. Clarke, J. Chem. Soc. Perkin I,2355, (1976).

EXAMPLE 46

A solution of bromobenzene (24.8 g) in ethyl ether (120 cc) is addeddropwise over approximately 1 hour to a suspension of magnesium turnings(3.85 g) in ethyl ether (100 cc). 4-Dimethylamino-1-phenyl-2-butyl-1-ol(10 g) in ethyl ether (30 cc) is added over approximately 15 minutes tothe black solution obtained. The reaction mixture is then refluxed for 3hours and 30 minutes, and then poured into a mixture of ice (400 g) anda saturated aqueous solution (200 cc) of ammonium chloride. The organicphase is separated; the aqueous phase is extracted with methylenechloride (2×200 cc); the organic phases are combined, dried overmagnesium sulphate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. The residue is purified by "flash"chromatography [eluent: methanol/ethyl acetate (60/40 by volume)],fractions 18 to 39 are combined and concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. After the residue has beenrecrystallized from isopropyl ether,4-dimethylamino-1,2-diphenyl-2-buten-1-ol (E) (3.9 g) is obtained in theform of white crystals melting at 113° C.

4-Dimethylamino-1-phenyl-2-butyn-1-ol can be prepared as follows: a1.55M solution (280 cc) of n-butyllithium in hexane is added to asolution of N,N-dimethylpropargylamine (33.2 g) in 1,2-dimethoxyethane(400 cc) kept under a nitrogen atmosphere at a temperature in the regionof -70° C. A solution of benzaldehyde (42.4 g) in 1,2-dimethoxyethane(100 cc) is added to the suspension obtained, at a temperature in theregion of -30° C. The reaction mixture is stirred for 30 minutes at atemperature in the region of 0° C., and then distilled water (20 cc) isadded. The suspension obtained is filtered. The solution is dried overmagnesium sulphate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) at 40° C. In this way,4-dimethylamino-1-phenyl-2-butyn-1-ol (72.3 g) is obtained in the formof a yellow oil [R_(f) =0.56; thin layer chromatography on alumina gel;eluent: ethyl acetate].

EXAMPLE 47

Benzoyl chloride (4.3 g) is added to a solution of4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (4.7 g) inanhydrous pyridine (60 cc) kept at a temperature in the region of 0° C.The reaction mixture is then stirred for 18 hours at a temperature inthe region of 20° C. and then poured into a saturated aqueous solution(300 cc) of sodium bicarbonate. The mixture obtained is extracted withethyl acetate (3×100 cc). The organic phases are combined, washed withwater (2×25 cc), dried over sodium sulphate and evaporated to drynessunder reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue obtained is then dissolved in isopropanol (50 cc). Thissolution is heated to boiling and a solution of oxalic acid (1.4 g) inisopropanol (10 cc) is added. The product which crystallises on coolingis separated off by filtration and then washed with isopropanol (3×3cc). By recrystallising the product obtained in this way fromisopropanol (90 cc), 4-benzoyloxy-1-dimethylamino-3,4-diphenyl-2-butene(Z) oxalate (5.3 g), melting at 170° C., is obtained.

4-Dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride can beprepared as in Example 1.

EXAMPLE 48

By proceeding as in Example 47 but starting from4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (4.5 g),acetyl chloride (3.5 g) and oxalic acid (1.35 g),4-acetoxy-1-dimethylamino-3,4-diphenyl-2-butene (Z) oxalate (3 g),melting at 156° C. after recrystallisation from isopropanol (300 cc) isobtained.

4-Dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride can beprepared as in Example 1.

EXAMPLE 49

Ethyl chloroformate (1.9 cc) is added to a solution of4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) (4.4 g) in the form offree base in toluene (50 cc). The mixture is stirred at a temperature of90°-95° C. for 3 hours and then cooled to ambient temperature. Theprecipitate formed is filtered off on a glass sinter and then washedwith isopropyl ether. In this way4-dimethylamino-1-ethoxycarbonyloxy-1,2-diphenyl-2-butene (Z)hydrochloride (3.86 g) is obtained in the form of a white solid meltingat 178° C.

4-Dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) can be obtained in a knownmanner from its hydrochloride prepared as in Example 1.

EXAMPLE 50

Crude 3-chloro-1-phenyl-1-phenylthio-1-propene (Z) (10.4 g) dissolved inethanol (40 cc) is added slowly at 0° C. to a solution oftert-butylamine (41.6 cc) in ethanol (100 cc) and stirring is continuedfor 14 hours at ambient temperature (22° C.). The reaction mixture isevaporated to dryness under reduced pressure (2.7 kPa) at 30° C. In thisway an orange-yellow residue is obtained which is purified by "flash"chromatography [eluent: methylene chloride/methanol (95/5 by volume)].Fractions 21 to 60 are combined and concentrated to dryness underreduced pressure (2.7 kPa) at 30° C. A solid is obtained which isrecrystallised from acetonitrile. In this way3-phenyl-3-phenylthio-1-tert-butylamino-2-propene (Z) (1.4 g) isobtained in the form of a white solid melting at 206° C.

3-Chloro-1-phenyl-1-phenylthio-1-propene (Z) can be obtained as follows:ethyl chloroformate (9.4 cc) is added to a solution of1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z) (17.6 g) in toluene(230 cc). The mixture is heated at 90° C. for 2 hours 30 minutes andthen evaporated to dryness under reduced pressure (2.7 kPa) at 30° C. Inthis way a pale yellow oil (21.8 g) is obtained containing the expected1-chloro-3-phenyl-3-phenylthio-2-propene (Z) mixed with ethyldimethylcarbamate formed during the reaction. This crude oil is employedwithout further purification in subsequent syntheses. NMR spectrum (60MHz, CDCl₃):

4.5 ppm, 2H: --CH₂ --

6.5 ppm, 1H: --CH═

6.9-75 ppm, 10H: aromatics

EXAMPLE 51

A solution of 3-chloro-1-phenyl-1-phenylthio-1-propene (Z) (17.2 g) inethanol (68 cc) is added dropwise to a 4.2N solution of ammoniacalethanol (150 cc) cooled to 0° C. After 14 hours' stirring at ambienttemperature, the reaction mixture is evaporated to dryness under reducedpressure (2.7 kPa) at 30° C. In this way a light yellow paste isobtained which is taken up in ethyl acetate (100 cc). The white solidwhich forms is separated off by filtration and recrystallised frommethyl ethyl ketone (250 cc). In this way a mixture (3.5 g) of 75%3-amino-1-phenyl-1-phenylthio-1-propene (Z) hydrochloride and 25%3-amino-1-phenyl-1-phenylthio-1-propene (E) hydrochloride is obtained inthe form of a white solid melting at 184° C.

EXAMPLE 52

A mixture of 4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) (0.6g) and a 4.2N solution (6 cc) of gaseous ammonia in ethanol is heated inan autoclave for 6 hours at 100° C. and then cooled to ambienttemperature. The reaction mixture is evaporated to dryness under reducedpressure (2.7 kPa) at 30° C. and then the residue obtained is purifiedby chromatography on a column of silica gel [eluent: methanol/ethylacetate (60/40 by volume)], 2 cc fractions being collected. Fractions 7to 10 are combined and concentrated to dryness under reduced pressure(2.7 kPa) at 30° C. In this way1-amino-3,4-diphenyl-4-ethoxycarbonyloxy-2-butene (Z) (0.1 g) isobtained in the form of a pale yellow oil [R_(f) : 0.15 ethylacetate/methanol (40/60 by volume)].

4-Chloro-1,2-diphenyl-1-ethoxycarbonyl-2-butene (Z) can be obtained asfollows: ethyl chloroformate (1.2 cc) is added to a solution of1-dimethylamino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (Z) in theform of free base in toluene (30 cc). The mixture is stirred for 1 hourand 30 minutes at 90° C. and then evaporated to dryness under reducedpressure (2.7 kPa) at 30° C. A residue is obtained which ischromatographed on a column of silica gel [eluent cyclohexane/ethylacetate (50/50 by volume)], 30 cc fractions being collected. Fractions 3to 6 are combined and concentrated under reduced pressure (2.7 kPa) at30° C. In this way 4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene(Z) (1.56 g) is obtained in the form of a light yellow oil [R_(f) =0.5,eluent cyclohexane/ethyl acetate (50/50 by volume)].

1-Dimethylamino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (Z) can beobtained in a known manner from its hydrochloride prepared as describedin Example 49.

EXAMPLE 53

Triethylamine (1.05 cc) and 1,3-propanedithiol (0.74 cc) are added to asolution of 4-azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) (0.5g) in methanol (7.5 cc). The mixture is stirred under a nitrogenatmosphere for 18 hours at ambient temperature. The reaction mixture isthen poured into water (10 cc), adjusted to pH 12 with an aqueoussolution of 4N sodium hydroxide and then extracted 3 times withmethylene chloride. The organic phase is dried over magnesium sulphate,filtered and then evaporated under reduced pressure (2.7 kPa) at 30° C.The residue obtained is purified by chromatography on silica gel[eluent: ethyl acetate/methanol (40/60 by volume)], 5 cc fractions beingcollected. Fractions 15 to 25 are evaporated to dryness under reducedpressure (2.7 kPa) at 30° C. In this way1-amino-3,4-diphenyl-4-ethoxycarbonyloxy-2-butene (E) (0.168 g) isobtained in the form of a pale yellow oil [R.sub. f =0.15, eluent:methanol/ethyl acetate (60/40 by volume)].

4-Azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) can be prepared asfollows: sodium azide (0.2 g) is added to a solution of4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) (0.65 g) inN,N-dimethylformamide (6.5 cc) cooled to 0° C., and the mixture is thenheated with stirring at 80° for 15 minutes. The reaction mixture is thencooled, water (10 cc) is added, and the mixture is extracted withmethylene chloride (3×10 cc). The organic phase is dried over magnesiumsulphate, filtered and then evaporated to dryness under reduced pressure(2.7 kPa) at 30° C. A residue is obtained which is chromatographed on acolumn of silica gel [eluent: ethyl acetate/ cyclohexane (30/70 byvolume)], 30 cc fractions being collected. Fractions 1 to 5 are combinedand concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.In this way 4-azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) (0.54g) is obtained in the form of a pale pink oil [R_(f) =0.7; eluent ethylacetate/cyclohexane (30/70 by volume)].

4-Chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) can be obtainedas in Example 52.

EXAMPLE 54

Potassium carbonate (0.1 g) is added to a solution of1-amino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (E) (0.02 g) inmethanol (1 cc). The suspension obtained is stirred for 70 hours at atemperature in the region of 20° C. The reaction mixture is filtered andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.The residue obtained is dissolved in methanol 0.2 cc); the solutionobtained is poured onto silica gel (1 g) in a column 5 mm in diameter.It is first eluted with methanol (3 cc), the corresponding eluate isdiscarded, and then with methanol (2 cc): the corresponding eluate isconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Inthis way 4-amino-1,2-diphenyl-2-buten-1-ol (E) (0.006 g) is obtained inthe form of a white powder. NMR spectrum (250 MHz) CDCl₃ :

3.20 ppm (d, 2H: ##STR32## 5.40 ppm (s, 1H: ##STR33## 6 ppm (t, 1H:##STR34##

1-Amino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (E) can be prepared asdescribed in Example 53.

EXAMPLE 55

Methyl isocyanate (2.1 cc) and 4-dimethylaminopyridine )10 mg) are addedto a solution of 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z)hydrochloride (10.5 g) in chloroform (150 cc). The reaction mixture isstirred for 18 hours at a temperature in the region of 20° C. and thentreated with a saturated aqueous solution (100 cc) of sodiumbicarbonate. The aqueous phase is separated, washed with methylenechloride (2×50 cc) and then the organic phases are combined, washed withwater (2×25 cc), dried over sodium sulphate and evaporated to drynessunder reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue obtained is then dissolved in isopropanol (100 cc); thissolution is heated to boiling and Å solution of oxalic acid (3.6 g) inisopropanol (50 cc) is added to it. The product which crystallises oncooling is separated off by filtration and then washed with isopropanol(3×5 cc). By recrystallisation of the product thus obtained from ethanol(150 cc), 1dimethylamino-4-methylcarbamoyloxy-3,4-diphenyl-2-butene (Z)oxalate (9.1 g), melting at 194° C., is obtained.

4-Dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride can beprepared as in Example 1.

EXAMPLE 56

Palladium on charcoal (10% weight/volume; 0.036 g) is added to asolution of 4-allylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride(0.5 g) in water (4.5 cc) and the mixture is stirred at a temperature of100° C. under nitrogen atmosphere for 18 hours. Palladium on charcoal(10% weight/volume; 0.018 g) is then added and heating under reflux iscontinued for 12 hours. After cooling to ambient temperature, thecatalyst is separated off by filtration and a 4N aqueous solution (5 cc)of sodium hydroxide is added to the solution, followed by sodiumchloride until saturated. The aqueous phase is extracted with methylenechloride (3×20 cc). The organic phase is dried over magnesium sulphate,filtered and then evaporated to dryness under reduced pressure (2.7 kPa)at 30° C. to produce a light yellow oil which is chromatographed on acolumn of silica gel (eluent: methanol), 2 cc fractions being collected.Fractions 22 to 30 are combined and concentrated to drynes under reducedpressure (2.7 kPa) at 30° C. 4-Amino-1,2-diphenyl-2-buten-1-ol (Z)(0.035 g) is obtained in the form of a white solid. NMR spectrum (250MHz, CDCl₃):

3.35 ppm (m, 2H: --CH₂ NH₂)

5.75 ppm (s, 1H: --CHOH--)

5.90 ppm (t, 1H: --CH═) ##STR35##

4-Allylamino-1,2-diphenyl-2-buten--ol (Z) can be obtained as describedin Example 34.

EXAMPLE 57

m-Chloroperbenzoic acid (4.7 g) is added to a solution of1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z) hydrochloride (6 g)in dichloromethane (68 cc), at 0° C. After 24 hours' stirring at 20° C.,additional m-chloroperbenzoic acid (4.7 g) is added and stirring iscontinued for 3 hours. The reaction mixture is poured into water (100cc); the solution is adjusted to pH 10 by adding a 35% strength aqueoussolution of sodium hydroxide and is taken up with methylene chloride.The organic phase is separated, dried over sodium sulphate, filtered andthen evaporated to dryness under reduced pressure (2.7 kPa) at 40° C. Inthis way a residue is obtained which is dissolved in ethanol (10 cc). A3N solution (6 cc) of hydrochloric acid gas in ethyl ether is added tothis solution. The solid which precipitates is separated off byfiltration and then recrystallised from a mixture of ethanol (60 cc) andacetonitrile (5 cc). In this way1-dimethylamino-3-phenyl-3-phenylsulphinyl-2-propene (Z) hydrochloride(2 g) is obtained in the form of white crystals melting at 268° C.(decomposition).

1-Dimethylamino-3-phenyl-3-phenylthio-2-propene (Z form) hydrochloridecan be obtained as described in Example 35.

EXAMPLE 58

By using a method similar to that described in Example 22, but startingfrom β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (10 g) and2-fluorobenzaldehyde (2.6 cc),4-dimethylamino-1-(2-fluorophenyl)-2-phenyl-2-buten-1-ol (Z)hydrochloride (3.5 g) is obtained in the form of a white powder meltingat 175° C. after recrystallisation from a mixture (90 cc) of isopropanoland isopropyl ether (60/40 by volume).

EXAMPLE 59

By using a method similar to that described in Example 22, but startingfrom β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and3-bromobenzaldehyde (5.6 cc),1-(3-bromophenyl)-4dimethylamino-2-phenyl-2-buten-1-ol (Z) hydrochloride(11.3 g ) is obtained in the form of a white solid melting at 188° C.after recrystallisation from isopropanol (200 cc).

EXAMPLE 60

By using a method similar to that described in Example 22, but startingfrom β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and fromo-tolualdehyde (5.78 g),4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol (Z)hydrochloride (10.2 g) is obtained in the form of a white powder meltingat 204° C. after recrystallisation from ethanol (100 cc).

EXAMPLE 61

By using a method similar to that described in Example 22, but startingfrom β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and fromo-anisaldehyde (6.5 g),4-dimethylamino-1-(2-methoxyphenyl)-2-phenyl-2-buten-1-ol (Z) (7.2 g) isobtained in the form of a white powder melting at 77° C. afterrecrystallisation from a mixture (85 cc) of petroleum ether andisopropyl ether (70/30 by volume).

EXAMPLE 62

By using a method similar to that described in Example 22, but startingfrom β-dimethylamino-3-methoxypropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (21.7 g) and frombenzaldehyde (5.4 cc),4-dimethylamino-2-(3-methoxyphenyl)-1-phenyl-2-buten-1-ol (Z)hydrochloride (11.9 g) is obtained in the form of a white solid meltingat 166° C. after recrystallisation from isopropanol (100 cc).

β-Dimethylamino-3-methoxypropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone can be prepared by a methodsimilar to that described in Example 22 for the preparation ofβ-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone, but starting from2,4,6-triisopropylbenzenesulphonylhydrazine (25.3 g) andβ-dimethylamino-3-methoxypropiophenone hydrochloride (20.7 g). In thisway β-dimethylamino-3-methoxypropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone hydrochloride (26.1 g) isobtained in the form of a white solid melting at 188° C.

β-Dimethylamino-3-methoxypropiophenone hydrochloride can be prepared bythe method described in German Pat. No. 2,360,455.

EXAMPLE 63

By using a procedure similar to that described in Example 22, butstarting from β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and fromcyclopropanecarboxaldehyde (3.37 g), an orange oil is obtained afterevaporation of the organic phases to dryness under reduced pressure(2.7kPa) at 30° C., which is purified by "flash" chromatography [eluent:ethyl acetate/methanol (8/20 by volume)]. After fractions 20 to 80 havebeen evaporated to dryness under reduced pressure (2.7 kPa) at 30° C.,an oil is obtained. This oil is dissolved in acetone (50 cc); oxalicacid (3.93 g) dissolved in acetone (50 cc) is added to the solutionobtained. The solid formed is separated off by filtration and thenrecrystallised from acetonitrile (80 cc). In this way1-cyclopropyl-4-dimethylamino-2-phenyl-2-buten-1-ol (Z) oxalate (7.2 g)is obtained in the form of a white powder melting at 127° C.

Cyclopropanecarboxaldehyde can be prepared by the method described by A.J. Mancuso, D. S. Brownfair, D. Swern, J. Org. Chem. 23, 4148, (1979).

EXAMPLE 64

By using a method similar to that described in Example 22 but startingfrom β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from α-tetralone(6.4 cc),1-(1-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)-3-dimethylamino-1-phenyl-1-propene(Z) (3.8 g) is obtained in the form of a white powder melting at 108° C.after recrystallisation from a mixture (65 cc) of petroleum ether andisopropanol (95/5 by volume).

EXAMPLE 65

By using a procedure similar to that described in Example 22 butstarting from β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and fromcyclohexanone (5 cc),1-(1-hydroxy-1-cyclohexyl)-3-dimethylamino-1-phenyl-1-propene (Z)hydrochloride (6 g) is obtained in the form of a white powder melting at197° C. after recrystallisation from a mixture (50 cc) of isopropanoland isopropyl ether (60/40 by volume).

EXAMPLE 66

By using a method similar to that described in Example 22, but startingthe β-dimethylaminopropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and fromisobutyraldehyde (3.47 g) 1-dimethylamino-5-methyl-3-phenyl-2-hexen-4-ol(Z) hydrochloride (5.6 g) is obtained in the form of a white powdermelting at 163° C. after recrystallisation from acetone (150 cc).

EXAMPLE 67

By using a method similar to that described in Example 22, but startingfrom α-(1-methyl-2-pyrrolidinyl)-acetophenone2,4,6-triisopropylbenzenesulphonylhydrazone (13 g) and from benzaldehyde(3.5 cc), 1,2-diphenyl-3-(1-methyl-2-pyrolidinyl-2-propen-1-ol (Z)hydrochloride (3.45 g) is obtained in the form of a white solid meltingat 240° C. after recrystallisation from ethanol (100 cc).

α-(1-Methyl-2-pyrrolidinyl)acetophenone2,4,6-triisopropylbenzenesulphonylhydrazone can be prepared by a methodsimilar to that described in Example 22 for the preparation ofβ-dimethylaminopropiophenone,2,4,6-triisopropylbenzenesulphonylhydrazone, but starting from2,4,6-triisopropylbenzenesulphonylhydrazine (30.6 g) andα-(1-methyl-2-pyrrolidinyl)acetophenone hydrochloride (28.3 g). In thisway, α-(1-methyl-2-pyrrolidinyl)acetophenone2,4,6-triisopropylbenzenesulphonylhydrazone hydrochloride (31.1 g) isobtained in the form of a white solid melting at 210° C.

α-(1-Methyl-2-pyrrolidinyl)acetophenone hydrochloride can be prepared bythe method described by A. S. Radwan, F. R. Melek, S. Negm, J. prakt.Chem., (1980), 322, 475.

EXAMPLE 68

A 1.9M solution (30.4 cc) of tert-butyllithium in pentane is added to asolution of β-dimethylamino-α-methylpropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (10.9 g) in1,2-dimethoxyethane (109 cc), kept under nitrogen atmosphere at atemperature in the region of -75° C. Once the addition has beencompleted the reaction mixture is warmed slowly to 15° C. When gasevolution has stopped, the reaction mixture is cooled to a temperaturein the region of -40° C. Benzaldehyde (4.2 g) is then added and stirringis continued for 20 minutes while the temperature is allowed to rise toapproximately -5° C. Distilled water (50 cc), an aqueous solution (7cc)of concentrated hydrochloric acid, and then ethyl ether (200 cc) areadded in succession. The organic phase is separated and then extractedwith a 4N aqueous solution of hydrochloric acid (2×25 cc). The aqueousphases are combined, made alkaline to a pH in the region of 10 with a 10N aqueous solution of sodium hydroxide and then extracted with ethylacetate (3×150 cc). The organic phases are combined, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 30° C. The orange oil obtained isdissolved in acetone (91 cc); a 5.6N solution (4.5 cc) of hydrochloricacid gas in ethyl ether is added to the solution obtained. The solidformed is separated off by filtration and then recrystallised from amixture (48 cc) of isopropanol and isopropyl ether (80/20 by volume). Inthis way 4-dimethylamino-1,2-diphenyl-3-methyl-2-buten-1-ol (Z)hydrochloride (1.85 g) is obtained in the form of a white powder meltingat 212° C.

β-Dimethylamino-α-methylpropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone can be prepared as follows:2,4,6-triisopropylbenzenesulphonylhydrazine (23.8 g) is added toα-methyl-β-dimethylaminopropiophenone hydrochloride (16.3 g) dissolvedin methylene chloride (150 cc) and acetic acid (5 cc). The solution isstirred at ambient temperature for 24 hours and is then poured intowater (50 cc). The aqueous phase is extracted with methylene chloride(2×50 cc) and then the organic phases are combined, dried over magnesiumsulphate, filtered and evaporated to dryness under reduced pressure (2.7kPa) at 40° C. to give a yellow oil which is crystallised in a mixture(120 cc) of ethyl acetate and isopropyl ether (50/50 by volume). In thisway β-dimethylamino-α-methylpropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone hydrochloride (16 g) isobtained in the form of a white solid melting at 147° C.

The base can be liberated from its hydrochloride as follows: thehydrochloride obtained previously is dissolved in water (100 cc) andthen a 4N aqueous solution of sodium hydroxide is added to the solutionobtained, up to a pH of 10, and the latter is then extracted with ethylacetate (3×75 cc). The organic phases are combined, dried over magnesiumsulphate, filtered and then evaporated to dryness under reduced pressure(2.7 kPa) at 40° C. In this way β-dimethylamino-α-methylpropiophenone2,4,6-triisopropylbenzenesulphonylhydrazone (13 g) is obtained, as thebase, in the form of a white solid melting at 113° C.

β-Dimethylamino-α-methylpropiophenone can be prepared by the methoddescribed by s. Miyano, H. Hokari and H. Hashimotor Bull. Chem. Soc.Japan, 55, 534 (1982).

EXAMPLE 69

An ethanol solution (100 cc) containing 33% of methylamine is added to asolution of4-chloro-1-ethoxycarbonyloxy-1-(3-fluorophenyl)-2-phenyl-2-butene (Z)(9.5 g) in ethanol (50 cc). After 2 hours'stirring in the absence oflight, the reaction mixture is evaporated under reduced pressure (2.7kPa) at 30° C. to give an oil. This oil is dissolved in distilled water(50 cc) and the solution obtained is made alkaline to pH 11 by adding a4N solution of sodium hydroxide, and is then extracted with ethyl ether(3×100 cc). The organic phases are combined, dried over magnesiumsulphate, filtered and then evaporated to dryness under reduced pressure(2.7 kPa) at 30° C. to give an orange oil. This oil is dissolved inethyl acetate (40 cc) and then a 5.7N solution (5 cc) of hydrochloricacid gas in ethyl ether is added to it. The solid formed is separatedoff by filtration and then recrystallised from acetonitrile (20 cc). Inthis way 1-(3-fluorophenyl)-4-methylamino-2-phenyl-2-buten-1-ol (Z)hydrochloride (3 g) is obtained in the form of a white solid melting at167° C.

4-Chloro-1-ethoxycarbonyloxy-1-(3-fluorophenyl)-2-phenyl-2-butene (Z)can be obtained as described in Example 52 for the preparation of4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene, but starting from1-dimethylamino-4-ethoxycarbonyloxy-4-(3-fluorophenyl)-3-phenyl-2-butene(Z) (26.2 g) and ethyl chloroformate (10.6 cc). After "flash"chromatography [eluent: cyclohexane/ethyl acetate (90/100 volume)] andevaporation of fractions 12 to 18 to dryness under reduced pressure (2.7kPa) at 30° C.,4-chloro-1-ethoxycarbonyloxy-1-(3-fluorophenyl)-2-phenyl-2-butene (Z)(21.1 g) is obtained in the form of a pale yellow oil [R_(f) =0.5;eluent: cyclohexane/ethyl acetate (50/50by volume)].

1-Dimethylamino-4-ethoxycarbonyloxy-4-(3-fluorophenyl)-3-phenyl-2-butene(Z) hydrochloride can be obtained as described in Example 49 for thepreparation of 4-dimethylamino-1-ethoxycarbonyloxy-1,2-diphenyl-2-butene(Z) hydrochloride but starting from4-dimethylamino-4-(3-fluorophenyl)-3-phenyl-2-buten-1-ol (Z) (12.6 g)and ethyl chloroformate (5.1 cc). In this way1-dimethylamino-4-ethoxycarbonyloxy-4-(3-fluorophenyl)-3-phenyl-2-butene(Z) hydrochloride, (7.7 g) is obtained in the form of a beige solidmelting at 160° C.

EXAMPLE 70

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.5cc), thiophenol (4.13 g) and sodium cyanoborohydride (1 g), and afterevaporating the organic phase to dryness under reduced pressure (2.7kPa) at 40° C., a yellow oil is obtained which is dissolved in a mixture(35 cc) of ethyl ether and ethanol (70/30 by volume). Oxalic acid (2.2g) is added to the solution obtained. The precipitate formed isseparated off by filtration and recrystallised from ethanol (60 cc). Inthis way 1-dimethylamino-3-(4-fluorophenylthio)-3-phenyl-2-propene (Z)oxalate (5.8 g) (containing 25% of its E isomer), is obtained in theform of a white solid melting at 133° C.

EXAMPLE 71

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (6.1 g), phosphorus oxychloride (3cc), 2-chlorothiophenol (5 g) and sodium cyanoborohydride (1.3 g), andafter evaporating the organic phase to dryness under reduced pressure(2.7 kPa) at 40° C., a yellow oil is obtained which is dissolved inisopropanol (20 cc). A 5.6N solution (7.8 cc) of hydrochloric acid gasin ethyl ether is added to this solution. The precipitate formed isseparated off by filtration and then recrystallised from isopropanol (20cc). In this way3-(2-chlorophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z)hydrochloride (2.5 g) is obtained in the form of a white solid meltingat 162° C.

EXAMPLE 72

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.5cc), 3-chlorothiophenol (4.13 g) and sodium cyanoborohydride (1 g), andafter evaporating the organic phase to dryness under reduced pressure(2.7 kPa) at 40° C., a residue is obtained which is dissolved in amixture (20 cc) of acetone and ethyl ether (50/50 by volume). A 5.6Nsolution (6 cc) of hydrochloric acid gas in ethyl ether is added to thissolution. The precipitate formed is separated off by filtration and thenrecrystallised from isopropanol (30 cc). In this way3-(3-chlorophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z)hydrochloride (2.6 g) is obtained in the form of a white solid meltingat 156°-157° C.

EXAMPLE 73

By using a method similar to that described in Example 35, but startingfrom 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.47cc), 4-methylthiophenol (3.55 g) and sodium cyanoborohydride (1 g), andafter evaporating the organic phase to dryness under reduced pressure(2.7 kPa) at 40° C., an orange oil is obtained which is dissolved inisopropanol (40 cc). A 5.6N solution (7 cc) of hydrochloric acid gas inethyl ether is added to this solution. The precipitate formed isseparated off by filtration and then recrystallised from isopropanol (40cc). In this way1-dimethylamino-3-(4-methylphenylthio)-3-phenyl-2-propene (Z)hydrochloride (3.3 g) is obtained in the form of a white solid meltingat 197°-198° C.

EXAMPLE 74

By using a method similar to that described in Example 50, but startingfrom 3 -chloro-1-phenyl-1-phenylthio-1-propene (Z) (45 g) and from amethanol solution (143 cc) containing 33% of methylamine, an orange oilis obtained after evaporation to dryness under reduced pressure (2.7kPa) at 30° C., which is dissolved in ethyl acetate (150 cc). A 5.6Nsolution (18.5 cc) of hydrochloric acid gas in ethyl ether is added tothis solution. The precipitate formed is separated off by filtration andthen recrystallised from isopropanol (70 cc). In this way1-methylamino-3-phenyl-3-phenylthio-2-propene (Z) hydrochloride (12.8 g)is obtained in the form of a white solid melting at 141° C.

EXAMPLE 75

A 1.5N solution (20 cc) of n-butyllithium in hexane is added to asolution of 3-bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z)(5.1 g) in pentane (50 cc) kept under nitrogen atmosphere at atemperature in the region of -78° C. and the mixture is stirred for 25minutes at -50° C. Benzaldehyde (4 cc) dissolved in pentane (6 cc) isthen added and stirring is continued for 30 minutes while thetemperature is allowed to rise to 25° C. Distilled water (80 cc) is thenadded followed by a 2N aqueous solution (30 cc) of hydrochloric acid.The aqueous phase is separated, washed with ethyl ether (3×25 cc),neutralised with a saturated aqueous solution of sodium bicarbonate, andthen extracted with ethyl ether (3×50 cc). The organic phases arecombined, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa) at 40° C. The oil obtained isdissolved in ethanol (30 cc). A 5.7N solution (5.7 cc) of hydrochloricacid gas in ethyl ether is added to this solution. The solid formed isseparated off by filtration and then recrystallised from isopropanol (80cc). In this way2-(3-chlorophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z)hydrochloride (3.7 g) is obtained in the form of a white solid meltingat 199° C.

3-Bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z) can be preparedby a method similar to that described in Example 16, but starting from1-(3-chlorophenyl)-3-dimethylamino-2-propen-1-one (44 g), phosphorusoxybromide (60 g) and sodium cyanoborohydride (7.9 g). After thereaction mixture has been evaporated to dryness under reduced pressure(2.7 kPa) at 30° C., a beige solid is obtained which is taken up inchloroform (400 cc). The suspension obtained is filtered and thefiltrate is evaporated to dryness under reduced pressure (2.7 kPa) at30° C. After the product thus obtained has been washed with isopropanol(75 cc), 3-bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z)hydrobromide (46 g) is obtained in the form of a white solid melting at146° C.

1-(3-Chlorophenyl)-3-dimethylamino-2-propen-1-one can be prepared by themethod described in U.S. Pat. No. 4,209,621.

EXAMPLE 76

Using a method similar to that described in Example 75, but startingfrom 3-bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z) (5.1 g), a1.5M solution (15 cc) of n-butyllithium in hexane and3,5-dichlorobenzaldehyde (5 g),2-(3-chlorophenyl)-1-(3,5-dichlorophenyl)-4-dimethylamino-2-buten-1-ol(Z) hydrochloride (2.1 g) is obtained in the form of a white solidmelting at 215° C. after recrystallisation from isopropanol (100 cc).

EXAMPLE 77

By using a procedure similar to that described in Example 75, butstarting from 3-bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z)(10.2 g), a 1.5M solution (40 cc) of n-butyllithium in hexane and3-fluorobenzaldehyde (9.9 g),2-(3-chlorophenyl)-4-dimethylamino-1-(3-fluorophenyl)-2-buten-1-ol (Z)hydrochloride (6.6 g) is obtained in the form of a white solid meltingat 200° C. after recrystallisation from isopropanol (85 cc).

EXAMPLE 78

By using a method similar to that described in Example 16, but startingfrom 3-bromo-3-(2-chlorophenyl)-1-dimethylamino-2-propene (Z) (34 g) incrude form (containing the E-isomer), a 1.5M solution (90 cc) ofn-butyllithium in hexane, and benzaldehyde (16 cc), and afterpurification by "flash" chromatography [eluent: ethyl acetate/methanol(50/50 by volume)] and concentration of fractions 18 to 25 to drynessunder reduced pressure (2.7 kPa) at 40° C., a residue is obtained whichis dissolved in ethyl acetate (20 cc). A 5.6N solution (4 cc) ofhydrochloric acid gas in ethyl ether is added to this solution. Theprecipitate formed is separated off by filtration and thenrecrystallised from a mixture (70 cc) of acetonitrile and ethyl acetate(43/57 by volume). In this way2-(2-chlorophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z)hydrochloride (2.9 g) is obtained in the form of a white solid meltingat 168° C.

3-Bromo-3-(2-chlorophenyl)-1-dimethylamino-2-propene (Z) can be preparedby a method similar to that described in Example 16, but starting from1-(2-chlorophenyl)-3-dimethylamino-2-propen-1-one (35.2 g), phosphorusoxybromide (48.4 g) and sodium cyanoborohydride (6.35 g). After thereaction mixture has been evaporated to dryness under reduced pressure(2.7 kPa) at 30° C., a solid is obtained which is taken up in chloroform(400 cc). The suspension obtained is filtered. Distilled water (100 cc)is added to the filtrate and separated off. The aqueous phase is madealkaline to pH 9 with a concentrated aqueous solution of sodiumhydroxide and is then extracted with chloroform (2×100 cc). Thechloroform phases are combined, dried over magnesium sulphate, filteredand then evaporated to dryness under reduced pressure (2.7 kPa) at 30°C. In this way a mixture (34 g) of the Z and E isomers of3-bromo-3-(2-chlorophenyl)-1-dimethylamino-2-propene is obtained in theform of a brown oil [R_(f) =0.68; eluent: dichloromethane/methanol (95/5by volume)].

1-(2-Chlorophenyl)-3-dimethylamino-2-propen-1-one can be prepared by themethod described in U.S. Pat. No. 4,209,621.

EXAMPLE 79

Triethylamine (60 cc) and 1,3-propanedithiol (43 cc) are added to asolution of 4-azido-1,2-diphenyl-2-buten-1-ol (22.7 g; mixture of 75% ofZ isomer and 25% of E isomer) in methanol (370 cc). The mixture isstirred under nitrogen atmosphere for 20 hours at a temperature in theregion of 20° C. and is then poured into distilled water (600 cc). Themixture is adjusted to pH 12 with a 10N aqueous solution of sodiumhydroxide and then extracted with methylene chloride (3×500 cc). Theorganic phase is dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 30° C. Theoil obtained is stirred with methylene chloride and the precipitateformed is separated off by filtration. The filtrate obtained isconcentrated to dryness under reduced pressure (2.7 kPa) at 30° C. togive a yellow oil which is purified by chromatography on silica gel[eluent: methanol/ethyl acetate/11N aqueous ammonia (60/38/2 byvolume)]. Elution is first carried out with 460 cc of eluent; thecorresponding eluate is discarded. Elution then continues with 360 cc ofeluent; the corresponding eluate is evaporated to dryness under reducedpressure (2.7 kPa) at 30° to C. to a give a yellow solid which isdissolved in a mixture (130 cc) of ethanol and ethyl ether (25/75 byvolume). A 3.5N solution (4.8 cc) of hydrochloric acid gas in ethylether is added to the solution obtained. The white solid formed isseparated off by filtration and then recrystallised from a mixture ofethanol (11 cc) and isopropyl ether (16 cc). In this way4-amino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (1.88 g) is obtainedin the form of a white powder melting at 180° C.

4-Azido-1,2-diphenyl-2-buten-1-ol (mixture of 75% of Z isomer and 25% ofE isomer) can be prepared as follows: potassium carbonate (117 g) isadded to a solution of 4-azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene(Z) (28.5 g) prepared as described in Example 53, in methanol (300 cc).The mixture is stirred for 16 hours in the absence of light at atemperature in the region of 20° C., and is then filtered. The filtrateis concentrated to dryness under reduced pressure (2.7 kPa) at 30° C.The oil obtained is dissolved in methylene chloride (300 cc) and thenwashed with distilled water (200 cc). The aqueous phase is adjusted topH 7 by adding a 2N aqueous solution of hydrochloric acid and thenextracted with methylene chloride (2×300 cc). The organic phases arecombined, dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure (2.7 kPa) at 30° C. In this way4-azido-1,2-diphenyl-2-buten-1-ol (21.77 g) (mixture of 75% of Z isomerand 25% of E isomer) is obtained in the form of a pale yellow oil [R_(f)=0.6; eluent: cyclohexane/ethyl acetate (70/30 by volume)].

The present invention also relates to the medicaments consisting of aproduct of general formula (I) in free form or in the form of a salt ofaddition with a pharmaceutically acceptable acid, in a pure state or inthe form of a composition in which it is associated with any otherpharmaceutically compatible product, which may be inert orphysiologically active. The medicaments according to the invention maybe administered by oral, parenteral or rectal route.

As solid compositions for oral administration use may be made oftablets, pills, powders (particularly in gelatin capsules or cachets) orgranules. In these compositions the active product according to theinvention is mixed with one or more inert diluents such as starch,cellulose, sucrose, lactose or silica. These compositions may alsocontain substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a colorant, a coating(coated pills) or a varnish.

As liquid compositions for oral administration, use may be made ofsolutions, suspensions, emulsions, syrups and elixirs which arepharmaceutically acceptable and contain inert diluents such as water,ethanol, glycerol, vegetable oils or paraffin oils. These compositionsmay also contain substances other than the diluents, for example wettingagents, sweeteners, thickeners, flavourings or stabilisers.

The sterile compositions for parenteral administration may preferably beaqueous or non-aqueous solutions, suspensions or emulsions. As a solventor vehicle, use may be made of water, propylene glycol, a polyethyleneglycol, vegetable oils, in particular olive oil, injectable organicesters, for example ethyl oleate or other suitable organic solvents.These compositions may also contain adjuvants in particular wettingagents, isotonising agents, emulsifiers, dispersants and stabilisers.The sterilisation may be carried out in various ways, for example byasepticising filtration, by incorporating sterilising agents in thecomposition, by irradiation or by heating. They may also be prepared inthe form of solid sterile compositions which may be dissolved at thetime of use in an injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules, which, in addition to the active product, contain excipientssuch as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

In human therapy the products according to the invention are especiallyuseful in the treatment of the syndromes of various depressive statesand of psychasthenic states. The dosages depend on the effect which isrequired and on the duration of the treatment; they are generallybetween 25 and 250 mg per day by oral, intramuscular or intravenousroute for an adult, in one or more doses.

In general, the medical practitioner will determine the dosage which heor she considers the most appropriate as a function of the age, weightand all the other factors pertaining to the individual to be treated.

The following examples, given without implying a restriction, illustratethe compositions according to the invention.

EXAMPLE A

Tablets containing a 25 mg dose of the active product and having thefollowing composition are prepared according to the usual method:

    ______________________________________                                        4-Dimethylamino-1,2-diphenyl-2-buten-1-ol (Z)                                                            32    mg                                           hydrochloride                                                                 Starch                     60    mg                                           Lactose                    50    mg                                           Magnesium stearate         2     mg                                           ______________________________________                                    

EXAMPLE B

An injectable solution containing 25 mg of active product and having thefollowing composition is prepared:

    ______________________________________                                        4-Methylamino-1,2-diphenyl-2-buten-1-ol (Z)                                                              25    mg                                           1 N Hydrochloric acid      0.1   cc                                           Injectable solution q.s.   2     cc                                           ______________________________________                                    

We claim:
 1. A 3-phenyl-2-propeneamine of the formula: ##STR36## inwhich R denotes hydrogen, halogen, alkyl, alkyloxy, alkylthio, amino,alkylamino, dialkylamino or trifluoromethyl, R₃ denotes hydrogen oralkyl; either R₄ and R₅ each denote hydrogen and R₁ and R₂, which areidentical or different, each denote hydrogen or alkyl which isunsubstituted or substituted by alkenyl of 2 to 4 carbon atoms, or R₁and R₂ form together with the nitrogen atom to which they are linked orsaturated heterocyclic radical of 4 to 7 ring atoms optionallycontaining another heteroatom selected from the group consisting ofoxygen, sulphur or nitrogen which is unsubstituted or substituted byalkyl; or R₄ denotes hydrogen, R₁ denotes hydrogen or alkyl and R₂ andR₅ together form an alkylene radical 3 or 4 carbon atoms; and either(i)A denotes phenyl which is unsubstituted or substituted by one or twosubstituents chosen from halogen, alkyl, alkyloxy, alkylthio, amino,alkylamino, dialkylamino, nitro and trifluoromethyl, pyridyl, benzyl orcycloalkyl of 3 to 6 carbon atoms, and Y denotes sulphur, sulphinyl,sulphonyl or a radical of the formula: ##STR37## in which R₆ denoteshydrogen or alkyl and R₇ denotes hydrogen, alkylcarbonyl,alkyloxycarbonyl, alkylaminocarbonyl or benzoyl, which is unsubstitutedor substituted by one or two substituents chosen from halogen, alkyl,alkyloxy, alkylthio, amino, alkylamino, dialkylamino, nitro andtrifluoromethyl, or (ii) Y and A together form a 1-hydroxycycloalkylradical the ring of which contains 5 or 6 carbon atoms, optionallyjoined to a benzene ring; and its pharmaceutically acceptable salts, theaforesaid alkyl radicals and alkyl parts containing 1 to 4 carbon atomseach as a straight or branched chain, in the form of any geometric oroptical isomer or any mixture thereof.
 2. A 3-phenyl-2-propeneamineaccording to claim 1 in which R denotes hydrogen, halogen, alkyl,alkyloxy, alkylthio, amino, alkylamino, dialkylamino or trifluoromethyl;R₃ denotes hydrogen or alkyl; and either R₄ and R₅ denote hydrogen andR₁ and R₂ which are identical or different, each denote hydrogen oralkyl unsubstituted or substituted by alkenyl of 2 to 4 carbon atoms, orR₁ and R₂ together form with the nitrogen atom to which they are linkeda saturated heterocyclic radical containing 4 to 7 ring atoms; or R₄denotes hydrogen, R₁ denotes hydrogen or alkyl and R₂ and R₅ togetherform alkylene of 3 or 4 carbon atoms; and either(i) A denotes phenylwhich is unsubstituted or substituted by one or two substituents chosenfrom halogen, alkyl, alkyloxy, and trifluoromethyl, pyridyl, benzyl orcycloalkyl of 3 to 6 carbon atoms, Y denotes sulphur, sulphinyl, or aradical of formula: ##STR38## in which R₆ denotes hydrogen or alkyl andR₇ denotes hydrogen, alkylcarbonyl, alkyloxycarbonyl, benzoyl oralkylaminocarbonyl, or (ii) Y and A together form a 1-hydroxycycloalkylradical the ring of which contains 5 or 6 carbon atoms, optionallycombined with a benzene, ring, in the Z or E form, the said alkylradicals and alkyl parts containing 1 to 4 carbon atoms each, as astraight or branched chain, and its pharmaceutically acceptable salts.3. A 3-phenyl-2-propeneamine according to claim 1 in which R denoteshydrogen, halogen, alkyl, alkyloxy, alkylthio, amino, alkylamino,dialkylamino or trifluoromethyl, R₃ denotes hydrogen, R₄ and R₅ denotehydrogen, and R₁ and R₂, which are identical or different, each denotehydrogen or alkyl unsubstituted or substituted by alkenyl of 2 to 4carbon atoms; and A denotes phenyl, which is unsubstituted orsubstituted by one or two substituents chosen from halogen and alkyl,pyridyl or cycloalkyl of 3 to 6 carbon atoms, Y denotes a sulphur atom,or a radical of formula: ##STR39## in which R₆ denotes hydrogen and R₇denotes hydrogen or alkylcarbonyl, in the Z form, the said alkylradicals and alkyl parts containing 1 to 4 carbon atoms each as astraight or branched chain, and its pharmaceutically acceptable salts.4. A compound according to claim 1 which is4-dimethylamino-1,2-diphenyl-2-buten-1-ol-(Z) and its pharmaceuticallyacceptable salts.
 5. A compound according to claim 1 which is4-methylamino-1,2-diphenyl-2-buten-1-ol-(Z) and its pharmaceuticallyacceptable salts.
 6. A compound according to claim 1 which is1-(3-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol-(Z) and itspharmaceutically acceptable salts.
 7. A compound according to claim 1which is 1-(3-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol-(Z)and its pharmaceutically acceptable salts.
 8. A compound according toclaim 1 which is1-(3-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol-(Z) and itspharmaceutically acceptable salts.
 9. A compound according to claim 1which is 4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol-(Z)and its pharmaceutically acceptable salts.
 10. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 as a base or apharmaceutically acceptable salt thereof in combination with one or morecompatible, pharmaceutically acceptable diluents or adjuvants.